EA041137B1 - DOSING DEVICE AND PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF RHINITIS - Google Patents

Description

This application claims the priority of Indian Patent Application No. 201821014426 filed April 16

2018 and U.S. Patent Application No. 15/903597, filed February 23, 2018, No. 15/842063, filed December 14, 2017, No. 15/716661, filed September 27, 2017, No. 15/691500, filed August 30, 2017 and

15/636120 filed June 28, 2017

Technical field

The present invention relates to a dosing device and a pharmaceutical composition for nasal administration to a human for the treatment of rhinitis, and more particularly to a dosing device with a pharmaceutical composition containing mometasone, its ester (e.g., mometasone furoate) or its salt, and olopatadine or its salt ( e.g. olopatadine hydrochloride).

State of the art invention

Rhinitis is a medical term for irritation and inflammation of the lining inside the nose. Rhinitis can cause additional symptoms such as sneezing, nasal itching, coughing, headache, fatigue, malaise, and cognitive impairment. There is a need for a convenient, efficient and reliable dosage device with a pharmaceutical composition having excellent efficacy in the treatment of rhinitis.

Statement of the Invention

The present invention relates to a dosing device for nasal administration of a pharmaceutical composition containing mometasone, an ester thereof (eg mometasone furoate) or a salt thereof, and olopatadine or a salt thereof (eg olopatadine hydrochloride). The dosing device and pharmaceutical composition are particularly suitable for the treatment of allergic rhinitis in humans. The combination of dosing device and pharmaceutical composition provides stable dosing of mometasone and olopatadine components. In one embodiment, the compositions contain mometasone furoate and olopatadine hydrochloride.

In one embodiment of the invention, the dosing device and the pharmaceutical composition for nasal administration to a human include (a) a container for the pharmaceutical composition; (b) a dispenser head for dispensing a pharmaceutical composition from a container, the dispenser head comprising at least a pump or valve mechanism, a supply channel, and a spray orifice; (c) a dip tube extending along the longitudinal axis of the container, the dip tube having a proximal end in communication with the dispenser head and an open distal end extending into the interior of the container; and (d) a pharmaceutical composition in a container in communication with the distal end of the dip tube, the pharmaceutical composition comprising mometasone, an ester or salt thereof, and olopatadine or a salt thereof. In one embodiment of the invention, the pharmaceutical composition is an aqueous suspension containing a hydrocolloid, wherein mometasone is present in particulate form and olopatadine is in dissolved form. In a preferred embodiment, the pharmaceutical composition contains an appropriate amount of hydrocolloid such that the pharmaceutical composition has a viscosity of from 10 centipoise to about 200 centipoise, or preferably from about 20 to about 150 centipoise. The pharmaceutical composition may contain from about 0.001 to about 0.075% by weight of mometasone, its ester (e.g. mometasone furoate) or its salt in the form of particles, and from about 0.5 to about 0.8% by weight of olopatadine or its salt ( e.g. olopatadine hydrochloride) in dissolved form. Also included is a cap to cover the tip of the dosing head.

In one aspect of the invention, the container has an interior bottom of a conical shape, wherein the interior of the bottom slopes downward from the side wall of the container toward the center. The center is located along the longitudinal axis of the container. The interior of the bottom may comprise an additional recessed at an angle centered around the longitudinal axis, the center being the lowest point of the interior of the bottom of the container. In this aspect of the invention, the distal end of the dip tube may extend into the well or may be positioned at the top of the well.

In yet another aspect of the present invention, the well of the interior bottom of the container may further comprise a groove. The groove additionally deepens the inner part of the bottom of the hole and runs across the longitudinal axis of the container. Accordingly, the inside of the bottom of the well in the center is the lowest point of the inside of the bottom of the container. In this aspect of the invention, the open distal end of the dip tube may extend into the groove or may be positioned at the top of the groove. Also in this aspect of the invention, the size of the groove that further deepens the inside of the well bottom does not affect the outside of the well bottom, as long as the deepening dimension of the groove is within the wall thickness of the well bottom.

In yet another aspect of the present invention, at least the well of the inner bottom of the container further comprises a groove. This groove further deepens the inside of the bottom of the well in an amount that exceeds the thickness of the wall of the bottom of the well, resulting in the modification of the outer bottom of at least the well. In this aspect of the invention, the auxiliary bulge with the groove therein protrudes from at least the outer portion of the bottom of the well. The auxiliary bulge also extends across the longitudinal axis of the container. In this aspect of the invention, the open distal end of the dip tube may extend into the groove or may be located at the top of the groove.

In yet another aspect of the invention, the dispenser head is defined externally by at least the end or wall of the tip and a side wall. A spray hole located in it is located on the end wall. In this aspect of the invention, the cap is detachably attached to the dispenser head to cover at least the spray opening. The cap contains a sealing sleeve that can extend from the inner surface of the cap and communicate tightly or tightly with the perimeter of the side wall of the dispenser head.

In yet another aspect of the invention, the inner diameter of the distal end of the sealing collar is smaller than the outer diameter of the sidewall of the dosing head at the junction of the sealing collar with the sidewall. This relationship helps create a seal where the cap and dispenser head enter the closed position. In this engagement, the distal end of the sealing sleeve deforms in the radial direction.

In this or another aspect of the invention, the sealing collar may have a wall thickness that decreases as the sealing collar extends away from the inside of the cap. The cap may further comprise on its inner surface one or more protruding tabs that snap onto the side wall of the dispenser head in order to securely hold the cap on the dispenser head in a closed position.

The above and below design features of the various components of the dispensing device can be selectively combined in various combinations, each of which is discussed in this document. In addition, the following characteristics of the pharmaceutical composition can be selectively selected for use with the dispenser.

In one aspect of the invention, the pharmaceutical composition contains from about 0.001 to about 0.075% by weight of mometasone, its ester (e.g., mometasone furoate), or a particulate salt thereof, and from about 0.5 to about 0.8% by weight of olopatadine or its salts (for example, olopatadine hydrochloride) in dissolved form. In this aspect of the invention, the composition may further comprise a hydrocolloid system, for example in an amount sufficient to inhibit phase separation for at least 24 hours when stored at 25±2° C. and 60±5% relative humidity. In one embodiment of the invention, the composition, when stored for 12 months at 25±2°C and 60%±5% relative humidity in a dispenser, has one or more of the following properties:

(i) the composition contains no more than 1% of the total amount of impurities (after storage);

(ii) the composition contains no more than 1% DMC (after storage);

(iii) the composition contains no more than 1% DMCF (after storage);

(iv) the composition contains no more than 1% α-hydroxyolopatadine (after storage);

(v) the composition contains no more than 1% of the E-isomer of olopatadine (after storage);

(vi) the composition contains no more than 1% olopatadine bound Compound B (after storage) and/or (vii) the composition contains no more than 0.42% other impurities of olopatadine (after storage).

In another aspect of the invention, the pharmaceutical composition contains from about 0.025 to about 0.05% by weight of mometasone, its ester (for example, mometasone furoate), or its salt in the form of particles, and from about 0.5 to about 0.8% by weight. weight of olopatadine or its salt (for example, olopatadine hydrochloride). In another aspect of the invention, the pharmaceutical composition contains from about 0.025 to about 0.05% by weight of mometasone, its ester (for example, mometasone furoate), or its salt in the form of particles, and from about 0.6 to about 0.7% by weight olopatadine or its salts. The pharmaceutical composition may further contain a hydrocolloid as described above.

In yet another aspect of the invention, the dispenser dispenses about 100 µl of the pharmaceutical composition with each actuation, with one actuation dispensing about 665 µg of olopatadine hydrochloride and about 25 or about 50 µg of mometasone furoate (preferably 25 µg of mometasone furoate).

In general, a dispensing device may include a container, a cap, and a dispenser head which may include a pump, a dip tube, a valve, an actuator, a supply passage, and a spray orifice. The pump is intended for dispensing a pharmaceutical composition through a dip tube into a valve through an actuator equipped with a spray orifice. The pharmaceutical composition is released in the form of a uniform spray. The valves may be continuous spray valves and/or metering valves. The valves can work in tandem with the actuator, making it easy to open and close the valve and achieve the desired spray pattern. Drives include, but are not limited to, spray drives, foam drives, jet drives, and specialty drives. The dosing device dispenses a nasal spray with the same dose of, for example, mometasone (eg, mometasone furoate) and olopatadine (eg, as olopatadine hydrochloride), with the dose being dosed each time the dosing device is actuated by the user.

- 2 041137

It may be necessary to pre-prime the dispenser, which is performed during the implementation of about 2-6 clicks, for subsequent stable dispensing of the composition on an ongoing basis. The droplet size of the nasal spray can be controlled by the size of the spray opening of the container. The size of the spray hole also affects the performance of the spray.

In one aspect of the invention, the pharmaceutical composition, when delivered by a nasal spray dispenser, is in the form of a spray with a longest axis of about 15-75 mm, a shortest axis of about 10-65 mm and an ellipticity of about 1-2.

Brief description of graphic materials

The present invention will be better understood with reference to the following description taken in conjunction with the drawings. For the purpose of illustrating the invention, the drawings depict certain embodiments of the invention. On graphic materials, the same numbers indicate the same elements. However, it should be noted that the invention is not limited to the exact shapes, sizes and tools shown:

Fig. 1 illustrates one embodiment of the invention of a dispenser container and a pharmaceutical composition according to the present invention, wherein the container has a flat bottom;

fig. 2 illustrates a cross-sectional view of another embodiment of a container for a dispenser and a pharmaceutical composition according to the present invention, wherein the container has a conical bottom;

fig. 3 illustrates a cross-sectional view of yet another embodiment of a dispenser container and a pharmaceutical composition according to the present invention, wherein the container has a conical bottom with an angled well;

fig. 4A and 4B illustrate a cross-sectional and bottom perspective view, respectively, of a further embodiment of the invention of a dispenser container and a pharmaceutical composition according to the present invention, wherein the container has a conical bottom with an angled well containing a groove extending below the bottom of the well. , in FIG. 4A and the auxiliary bulge shown outside under the well in FIG. 4B;

fig. 5A and 5B illustrate a cross section and an exploded partial view, respectively, of one embodiment of a protective cap for a dispenser and a pharmaceutical composition according to the present invention, the cap being shown in a closed position on the dispenser head; and also FIG. 6 illustrates one embodiment of the invention of a dispensing device of said dispensing device and a pharmaceutical composition in accordance with the present invention.

Detailed description of the invention

The present invention relates to a dosage device and a pharmaceutical composition for nasal administration to a human for the treatment of rhinitis; and more specifically, to a dispenser with a pharmaceutical composition containing mometasone, its ester, or its salt, and olopatadine, or its salt.

In one embodiment of the invention, the dosing device and the pharmaceutical composition for nasal administration to a human comprise (a) a container for the pharmaceutical composition; (b) a dispenser head for dispensing a pharmaceutical composition from a container, the dispenser head comprising at least a pump or valve mechanism, a supply channel, and a spray orifice; (c) a dip tube extending along the longitudinal axis of the container, the dip tube having a proximal end in communication with the dispenser head and an open distal end extending into the interior of the container; and (d) a pharmaceutical composition in a container in communication with the distal end of the dip tube, the pharmaceutical composition comprising mometasone, an ester thereof (eg mometasone furoate) or a salt thereof, and olopatadine or a salt thereof (eg olopatadine hydrochloride). In one embodiment of the invention, the pharmaceutical composition is an aqueous suspension containing a hydrocolloid, wherein mometasone, its ester (for example, mometasone furoate) or its salt is present in the form of particles, and olopatadine or its salt (for example, olopatadine hydrochloride) is in dissolved form. In a preferred embodiment, the pharmaceutical composition contains an appropriate amount of hydrocolloid such that the pharmaceutical composition has a viscosity of 10 to about 200 centipoise, or preferably about 20 to about 150 centipoise. The pharmaceutical composition may contain from about 0.001 to about 0.075% by weight of mometasone, its ester (for example, mometasone furoate), or its salt in the form of particles, and from about 0.5 to about 0.8% by weight of olopatadine or its salt (for example , olopatadine hydrochloride) in dissolved form. Also included is a cap to cover the tip of the dosing head.

In one aspect of the invention, the container may have an interior bottom that is conically shaped, with the interior bottom sloping downward from the side wall of the container toward the center. The center is located along the longitudinal axis of the container. The interior of the bottom may include an additional recessed at an angle centered around the longitudinal axis, the center being the lowest point of the interior of the bottom of the container. In this aspect of the invention, the distal end of the dip tube may extend into the well or may be positioned at the top of the well.

In yet another aspect of the invention, the dispenser head is defined externally by at least the end or wall of the tip and a side wall. A spray hole located in it is located on the end wall. In this aspect of the invention, the cap is detachably attached to the dispenser head to cover at least the spray opening. The cap contains a sealing sleeve that extends from the inner surface of the cap and communicates tightly or tightly with the perimeter of the side wall of the dispenser head.

In a further aspect of the invention, the pharmaceutical composition comprises from about 0.001 to about 0.075% by weight of mometasone, its ester (e.g., mometasone furoate), or a particulate salt thereof, and from about 0.5 to about 0.8% by weight of olopatadine or its salts (for example, olopatadine hydrochloride) in dissolved form. In this aspect of the invention, the composition may further comprise a hydrocolloid system, for example in an amount sufficient to inhibit phase separation for at least 24 hours when stored at 25±2° C. and 60±5% relative humidity. In one embodiment of the invention, the composition, when stored for 12 months at 25±2°C and 60%±5% relative humidity in a dispenser, has one or more of the following properties:

(i) the composition contains no more than 1% of the total amount of impurities (after storage);

(ii) the composition contains no more than 1% DMC (after storage);

(iii) the composition contains no more than 1% DMCF (after storage);

(iv) the composition contains no more than 1% α-hydroxyolopatadine (after storage);

(v) the composition contains no more than 1% of the E-isomer of olopatadine (after storage);

(vi) the composition contains no more than 1% olopatadine-bound Compound B (after storage); and/or (vii) the composition contains no more than 0.42% other impurities of olopatadine (after storage).

In yet another additional aspect of the invention, the pharmaceutical composition contains from about 0.025 to about 0.05% by weight of mometasone, its ester (for example, mometasone furoate) or its salt in the form of particles, and from about 0.5 to about 0.8% by weight of olopatadine or its salt (for example, olopatadine hydrochloride). In this aspect of the invention, the pharmaceutical composition may further comprise a hydrocolloid.

In general, a dispenser may include a container, a cap, and a dispenser head which may include a pump, a dip tube, a valve, an actuator, a delivery port, and a spray orifice. The pump is intended for dispensing a pharmaceutical composition through a dip tube into a valve through an actuator equipped with a spray orifice. The pharmaceutical composition is released in the form of a uniform spray. The valves may be continuous spray valves and/or metering valves. The valves can work in tandem with the actuator, making it easy to open and close the valve and achieve the desired spray pattern. Drives include, but are not limited to, spray drives, foam drives, jet drives, and specialty drives. The dosing device dispenses a nasal spray with the same dose of mometasone (eg, mometasone furoate) and olopatadine (eg, olopatadine hydrochloride), with the dose being dosed each time the dosing device is actuated by the user.

In one aspect of the invention, the dispenser dispenses about 100 µl of the pharmaceutical composition with each actuation, with one actuation dispensing about 665 µg of olopatadine hydrochloride and about 25 µg or about 50 µg of mometasone furoate, preferably about 25 µg of mometasone furoate.

In yet another aspect of the present invention, it may be necessary to pre-prime the dispenser, which is performed during the implementation of about 2-6 clicks, for subsequent stable dispensing of the composition on an ongoing basis. The droplet size of the nasal spray can be controlled by the size of the spray opening of the container. The size of the spray hole also affects the performance of the spray.

Definitions

The term effective amount, when used in connection with an active ingredient, means the amount of the active ingredient which, when administered to a patient for the treatment of rhinitis, produces the intended therapeutic effect in the patient. The term active ingredient (used interchangeably with the terms active ingredient or active pharmaceutical ingredient or drug) as used herein includes mometasone furoate or a salt thereof, and olopatadine or a salt thereof. An effective amount of mometasone furoate or a salt thereof may range from about 0.01 mg to about 10 mg, or preferably from about 0.02 mg to about 5 mg. An effective amount of olopatadine or a salt thereof may vary from about 0.05 mg to about 20 mg, or preferably from about 0.1 mg to about 15 mg.

In an aspect of the present invention for daily nasal administration, an effective amount of mometasone furoate or a salt thereof may range from about 10 to about 500 μg, or preferably from about 20 to about 400 μg, and for olopatadine or a salt thereof may vary from about 50 to about 7000 μg or preferably from about 100 to about 5400 micrograms.

The terms "salt" or "pharmaceutically acceptable salt" means those salts that are medically suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions and a reasonable benefit / risk ratio, and are also effective for them. intended use. Typical acid addition salts include hydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate , tartrate, ascorbate, glucoheptonate, lactobionate and lauryl sulfate salts. Exemplary alkali or alkaline earth metal salts include sodium, calcium, potassium and magnesium salts.

As used herein, the term treatment or treatment includes the prevention, alleviation, prevention, amelioration or suppression of a disorder modulated by mometasone, an ester or salt thereof, or olopatadine or a salt thereof, or a combination of both in mammals.

The term pharmaceutically acceptable excipients refers to any of the components of a pharmaceutical composition, other than the active ingredients, that are approved by regulatory authorities or are generally considered safe for human or animal use.

As used herein, the term average particle size (or used as a synonym for the term average particle size) refers to a distribution of particles, where about 50 vol.% of all particles measured are smaller than the specified average particle size, and about 50 vol. % of all measured particles have a particle size greater than the specified average particle size value.

This can be defined in terms of D ₅₀ or d( ₀ , ₅ ). The average particle size can be measured using various techniques such as microscopy, laser diffraction, photon correlation spectroscopy (PCS) and the Coulter method.

The term hydrocolloid refers to a colloidal system in which hydrophilic colloidal particles (eg, hydrophilic polymers) are dispersed in water. The hydrocolloid system can exist in a gel state or in an ash (liquid) state. In suspension formulations, hydrocolloids act as thickening, stabilizing and suspending agents. Non-limiting examples of hydrocolloids include xanthan gum, gum arabic, guar gum, locust bean gum, alginate, starch, agar-agar, carrageenan, gelatin, Avicel RC591® (a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose) and cellulose derivatives (e.g., sodium carboxymethyl cellulose) . Preferably the hydrocolloid contains xanthan gum or sodium carboxymethyl cellulose.

As used herein, the term α-hydroxy-olopatadine olopatadine refers to the term (Z)-2-{11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2}-2-hydroxyacetic acid.

As used herein, the E-isomer of olopatadine refers to the term 11[(E)-3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid.

As used herein, the term olopatadine-related compound B refers to (Z)-3-{2-(carboxymethyl)dibenzo[b,e]oxepin-11(6H)-ylidene}-N,N-dimethylpropane-1-amine oxide.

As used herein, the term 8-DM mometasone refers to the term (9β,11βepoxy-17α,21-dihydroxy-16a-methyl pregna-1,4-diene-3,20-dione).

The term mometasone DMC as used herein refers to the term (21-chloro9b,11b-epoxy, 17a,-hydroxyl-16a-methyl-pregna-1,4-diene-3,20-dione).

As used herein, the term mometasone DMCF refers to the term (21-chloro9β,11β-epoxy-16a-methyl-3,20-dioxo-pregna-1,4-dien-17-ylfuran-2-carboxylate).

The term onset of action is the point at which patients can reasonably expect a significant reduction in their allergic rhinitis symptoms (e.g., a significant reduction in the Retrospective General Rhinitis Symptoms Scale (rTNSS), the Instantaneous Generalized Rhinitis Symptoms Scale (iTNSS), or the Retrospective common eye symptoms (rTOSS)). Statistically, this is the first time point after treatment initiation that a drug shows a change greater than placebo treatment from entry into the study at the primary efficacy endpoint. This statistically significant difference between drug and placebo is maintained for a period (eg, 4 hours) from this point forward. See Guidance for Industry, Allergic Rhinitis: Clinical Development Programs for Drug Products, US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), April 2000.

The term faster onset of action refers, in one embodiment of the present invention, to a statistically significant faster decrease in one or more parameters associated with the treatment of allergic rhinitis in a patient, such as a statistically significant faster decrease in the Retrospective General Rhinitis Symptoms Scale (rTNSS) score, instantaneous the patient's global symptom score (iTNSS) score or the patient's retrospective overall eye symptom score (rTOSS) score.

The term advertising refers to the notification, informing and/or notification of one or more persons of information (for example, the effectiveness or time of onset of action of a pharmaceutical product for the treatment or reduction of symptoms), for example, by the media, including, but not limited to, newspaper, magazine and online advertising, commercials and billboards. As used herein, the term advertising also includes a labeling claim for a pharmaceutical product that a pharmaceutical product can treat or relieve symptoms.

The term marketing refers to the act or process of selling a product, including, but not limited to, any offer to sell or sell a product, as well as advertising.

Dosing device

A dosing device for nasal administration to a human comprises (a) a container for a pharmaceutical composition; (b) a dispenser head for dispensing a pharmaceutical composition from a container, the dispenser head comprising at least a pump or valve mechanism, a supply channel, and a spray orifice; (c) a dip tube extending along the longitudinal axis of the container, the dip tube having a proximal end in communication with the dispenser head and an open distal end extending into the container. Cap may or may not be included.

The dispenser container may be round or oval; preferably, the container is round. The container may optionally have a flat bottom, or generally has a conical bottom. The conically shaped bottom slopes downward from the side wall of the container towards the center of the bottom, the center being the lowest point of the bottom of the container. The center of the bottom is preferably located along the longitudinal axis of the container.

There is a dip tube inside the container. In an embodiment of the invention of a container with a flat bottom, the distal (open) end of the dip tube is located near the flat bottom. In an embodiment of the invention of the conical container, the distal end of the dip tube is located in the conical portion (down at the bottom point) of the container. Positioning the distal end of the dip tube as close as possible to the bottom of the container bottom helps to avoid remaining dead volume in the container during multiple actuations (especially when the container is close to empty).

Typically, the conical bottom may further have an auxiliary bulge or angled dimple located about the longitudinal axis between the side and the center of the container, whereby the center provides an even lower point on the inside of the bottom of the container. Accordingly, the well accommodates the distal end of the dip tube for more efficient reduction of residual dead volume.

Flat bottom, conical bottom and recessed cone bottom, each of these options can be placed and supported on a support bowl having a flat closed bottom. The support bowl can be snapped onto the bottom of the container, where the upper open end of the support bowl is equipped to accommodate a corresponding container bottom.

Fig. 1 illustrates one embodiment of a dispenser container according to the present invention. The container 110 has a flat bottom 120. The flat bottom 120 of the container 110 rests on a support cup 140 that has a flat outer bottom surface in order to secure the container for easy storage.

Fig. 2 illustrates another embodiment of the invention of the dispenser container. The container 210 has a cone-shaped bottom 220 having a bottom point 230 on the inside. The bottom point 230 can accommodate the residual volume of the pharmaceutical composition 260. The cone-shaped bottom 220 is shown mounted on a support cup 240 that has a flat bottom surface to fix the container in the desired location.

The dip tube 250 is located within the container 210 and has a distal (open) end located at the low point 230 of the container 210. This particular configuration of the conical bottom 220 having the distal end of the dip tube 250 as close as possible to the low point 230 of the conical bottom 220 allows, at low residual volumes of the pharmaceutical composition 260, with multiple actuations of the dosing device, to provide a dose volume, especially in cases where the contents of the container 210 are close to depletion.

Fig. 3 illustrates a further embodiment of the invention of the dispenser container. Container 310 has a generally conical bottom 320 having an angled dimple 325 located around the longitudinal axis L of container 310. Dimple 325 recessed between the side of container 310 and the center of container 310 forms a center providing a low point 330 for the interior of the bottom of the container. 310. Similar to the above, the low point 330 can accommodate the residual volume of the pharmaceutical composition 360. This embodiment of the invention is again shown mounted on a support cup 340 which has a flat bottom surface to secure the container in the desired location.

In yet another further embodiment of the invention, the dispenser container as shown in FIG. 3, the bottom of the well 325 has a groove 365 located within it. The groove 365 further deepens the interior of the bottom of the well 325. In this embodiment, the size of the groove 365 does not affect the outside of the bottom of the well 325 (or container 310). As shown in FIG. 3, the outside of the bottom of the container 310 takes the shape and contour of the well 325. The height (or size of the recess) of the groove 365 is within the wall thickness of the bottom of the well 325 (and the container 310). Within the recess 325, a groove 365 extends laterally transverse to the longitudinal axis L of the container 310.

Within container 310 is dip tube 350. In an embodiment of container 310 having only well 325 (i.e., no groove 365 within well 325), the distal (open) end of dip tube 350 is located at the low point 330 of well 325. In an embodiment, of the invention of a container 310 having a well 325 with an internal groove 365 in it, the distal (open) end of the dip tube 350 extends into the groove 365 or extends to the inside of the bottom of the well 325 (just at the top of the groove 365, as shown in Fig. 3 ). The bottom of the groove 365, located on the longitudinal axis L of the container 310, becomes the low point 330 for the composition 360 in the container 310. A dip tube 350 extending into the groove 365 or extending to the inside of the bottom of the groove 325 (only at the top of the groove 365) ensures that the low residual volumes of the pharmaceutical composition 360 over multiple actuations of the dispensing device provided sufficient dose volume, especially in cases where the contents of the container 310 were close to depletion.

Fig. 4A illustrates a cross section of a dispenser container in yet another further embodiment of the invention. Fig. 4B illustrates a bottom perspective view of an outer embodiment of a dispenser container, with the outer embodiment of the container shown in FIG. 4B may be used with one or more of the interior container embodiments described above and below (for example, the exterior container embodiment of FIG. 4B may be used with the interior container embodiments of FIG. 3 or 4A).

In cross section in Fig. 4A, container 410 has a conical-shaped bottom 420 having an angled recess 425 located about the longitudinal axis L of container 410. The recess 425, recessed between the side of container 410 and the center of container 410, forms a center providing a low point 430 for the interior of the bottom of container 410. In this embodiment, the groove 465 extends below the bottom of the well 425 (shown in dotted lines in Figure 4A), deepening the bottom point 430 of the inside of the bottom of the container 410 below the bottom of the well 425.

In this aspect of the invention, when the groove 465 extends below the bottom of the well 425, expansion of the outside of the bottom of the container 410 is required. 4B, further deepening the outside of the bottom of the recess 425. In this embodiment, the groove 465 extends laterally transverse to the longitudinal axis L of the container 410 in an amount greater than the diameter of the recessed recess 425. As best illustrated in FIG. 4B, the outer portion of the bottom of the container 410 takes the shape and contour of the auxiliary bulge 470 rounded around the (semi-circular) well 425.

As shown in FIG. 4A, dip tube 450 is located within container 410 and has a distal (open) end extending into groove 465 or extending to the bottom of well 425 (just at the top of groove 465, as shown in FIG. 4A). The inside of the bottom of the groove 465, located on the longitudinal axis L of the container 410, becomes the low point 430 for the composition 460 in the container 410. A dip tube 450 extending into the groove 465 or extending to the bottom of the groove 425 (only at the top of the groove 465) makes it possible to ensure that the low residual volumes of pharmaceutical composition 460 across multiple dispenser actuations ensured dose volume, especially in cases where container 410 was close to depletion.

As noted above, the outer embodiment of the container 410 shown in FIG. 4B may include an inner embodiment of the container 410 shown in FIG. 4A, or may contain an inner embodiment of the container 310 shown in FIG. 3. The outdoor embodiment of the invention shown in FIG. 4B, including auxiliary bulge 470, provides structural support for the bottom of the container, regardless of the inner container embodiment used. For example, in FIG. 3, auxiliary thickening 470 provides structural support for the outside of the bottom

- 7 041137 container 310, where the wall thickness of the bottom of the well 325 is reduced due to the groove 365. As illustrated in FIG. 4A, the auxiliary bulge 470 is necessary because the groove 465 deepens below the normal dimension of the bottom of the well 425. In this aspect of the invention, the present invention contemplates adding a secondary bulge to the outside of the bottom of the container, regardless of the characteristics of the inside of the bottom of the corresponding container.

The container can be made from any polymeric substance. In such embodiments, suitable polymers include, but are not limited to, polyethylene, polypropylene (PP), polystyrene (PS), nylon (Ny), polyvinyl chloride (PVC), polyethylene terephthalate (PET), polycarbonate (PC), polyoxymethylene (POM) , polysulfone (PSF), polyethersulfone (PES), polyacrylate (PAR) and polyamide (PA). In some embodiments, the polymer is a polyethylene, in particular medium density polyethylene (MDPE) (or branched polyethylene) or high density polyethylene (HDPE) (or linear polyethylene). In one embodiment of the invention, the bottle is made from high density polyethylene (HDPE).

The container may have an inert coating on its inner surface in order to avoid any interaction of the container component with the pharmaceutical compositions in accordance with the present invention.

The dispensing device according to the present invention further comprises a cap equipped to close the dispensing head of the dispensing device. The cap is made of polymeric substances, which are described above. Preferably the cap is an Antilop cap, also known as an Anti-Loss On Priming cap. The cap has a sealing element extending from the interior of its top wall, the sealing element providing a seal between the cap and the spray opening of the dosing head. The design of the sealing element around the distal end of the dosing head and near the spray opening of the dosing head prevents the distal end of the dosing head from drying out and prevents interruptions in the delivery of the pharmaceutical composition from the dosing head upon accidental actuation.

Fig. 5A and 5B illustrate a cross-sectional and partial exploded view, respectively, of a protective cap 510 in accordance with the present invention on a dispenser head 515. The exploded view of FIG. 5B is a separate part according to FIG. 5A. Fig. 5A and 5B illustrate the cap in a closed, impermeable, or sealed position on a dispenser head 515. The dispenser head 515 may be frustoconical in shape, but typically has the shape of a typical nasal spray actuator.

The distal end of the dispenser head 515 includes a spray orifice 517 in the end or end wall 519 of the dispenser head 515, with the spray orifice 517 located at the end of the delivery channel 521. 525 to connect the 515 dosing head to a pump or valve (not shown). Near the end or end wall 519 of the dispenser head 515 is the side wall 527 of the dispenser head 515 and there is a rounded edge between them.

The cap 510 includes a sealing element or sleeve 530 that protrudes from the inside of the top wall 532 of the cap 510. The sealing element 530 may be an annular sealing flange or sleeve. The sealing member 530 is in fluid or tightly sealed communication with the side wall 527 of the dispenser head 515 when the cap 510 is in the closed position. The sealing element 530 may be integral with the cap.

The sealing member or sleeve 530 may have a thickness that decreases as the sealing member protrudes from the inside of the top wall 532 of the cap 510, as is readily shown in FIG. 5B, where the sealing element 530 is thicker at the proximal end 534 (at the point of connection with the inside of the top wall 532 of the cap 510) than at the distal end 536. The sealing element 530 provides the flexibility to provide a seal or seal to the side wall 527 of the dispenser head. 515. After the cap 510 is closed, the distal end 536 of the sealing element 530 is connected to the side wall 527 by a friction fit to create a seal or airtight fit. In one embodiment, the inside diameter of the distal end 536 of the sealing element 530 is smaller than the outside diameter of the side wall 527 of the dispenser head 515 at the junction of the sealing element 530 with the dispenser head 515 in order to provide a seal between the sealing element 530 and the dispenser head 515. In this case, due to the flexibility of the distal end 536 of the sealing member 530, the distal end 536 of the sealing member 530 deforms in the radial direction when the cap 510 is in the closed position.

The inside of the cap 510 and/or the outside of the side wall 527 of the dispenser head 515 may further include one or more protrusions 538 that snap into place with engaging latches to securely hold the cap 510 on the dispenser head 515 when the cap 510 is in the closed position. . With the cap 510 in the locked closed position on the dispenser head 515, the inside of the top wall 532 of the cap 510 does not contact the end wall 519 of the dispenser head 515. Only the sealing member 530 contacts the side wall 527 of the dispenser head 515 tightly or tightly.

Accordingly, when the cap 510 is in the closed position, only a small amount of air is present between the end wall 519 of the dispenser head 515, the inside of the top wall 532 of the cap 510, and the sealing member 530. This amount of air prevents any liquid inside the spray hole 517 from evaporating and/or drying out.

Fig. 6 illustrates one embodiment of a dispensing device 605 in accordance with the present invention. The dispenser 605 shown in FIG. 6 contains an optional cap 611, a container 610, a dispenser head 615, a pump 619, and a dip tube 650 (not shown in FIG. 6). The pump 619 is adequate for dispensing a stable fixed dose of a pharmaceutical composition in accordance with the present invention from a container 610 through a dip tube 650 (not shown in FIG. 6) into the dispenser head 615 and beyond the spray orifice. A valve may be included to release the composition from the spray orifice in the dispenser head as a spray. The pump 619 may include a pre-compression pump such as the model VP3 or VP7, or a modified version thereof manufactured by Valois SA. For example, the dispenser 605 is compliant for dispensing a nasal spray with a uniform dosage of mometasone (eg, mometasone furoate) and olopatadine (eg, olopatadine hydrochloride) each time the dispenser is actuated by the user.

The dispensing device 605 may include a valve for dispensing a spray of a stable fixed dose of the composition from a spray orifice. The valves may include, but are not limited to, continuous spray valves and metering valves. Opening and closing of the valve is facilitated by pressing the dosing head. Various types of actuation include, but are not limited to, spray drives, foam drives, jet drives, and specialty drives.

As further described in more detail below, in some embodiments, the dispenser is adequate to dispense about 100 μl of the pharmaceutical composition with each actuation, with one actuation dispensing about 665 μg of olopatadine hydrochloride and about 25 μg or about 50 μg mometasone furoate, preferably 25 µg mometasone furoate.

pharmaceutical composition

A pharmaceutical composition for nasal administration to a human may contain from about 0.001 to about 0.075 wt. e.g. olopatadine hydrochloride). The pharmaceutical composition is stable and typically contains a fixed dose of mometasone, its ester (eg mometasone furoate) or salt thereof, and olopatadine or its salt (eg olopatadine hydrochloride).

The pharmaceutical composition may be in the form of a solution or suspension. In one preferred embodiment of the invention, 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 is present in particulate form and olopatadine or its salt (e.g. olopatadine hydrochloride) present in dissolved form. Mometasone, its ester (eg, mometasone furoate) or salt thereof, and olopatadine or salt thereof (eg, olopatadine hydrochloride) may be present in a weight ratio of from about 1:3 to about 1:106, or from about 1:5 to about 1:53, or preferably about 1:5 to about 1:36.

The composition preferably also contains a hydrocolloid. In one embodiment of the invention, the composition is a suspension and contains a sufficient amount of hydrocolloid to prevent phase separation (i.e. separation of particles and solution) after 3 or 6 months of storage at a temperature of 25±2°C and relative humidity (RH) 60±5% , or at a temperature of 40±2°C and relative humidity (RH) 75%±5%. In one embodiment of the invention, the aqueous pharmaceutical composition is a single-phase suspension that remains a single-phase suspension even after 3 or 6 months of storage at 25±2°C and 60±5% relative humidity, or at 4±2°C and relative humidity 75%±5%.

The term stable, as used in connection with aqueous suspensions, refers to a composition that, when shaken and then stored for at least 24 hours at ambient conditions, does not show phase separation upon visual inspection. Preferably, such a stable composition does not show phase separation for at least 3 days, or at least 5 days, or at least 7 days. In one aspect of the invention, the stable composition exhibits, after shaking (e.g., for 1 minute) and visual inspection, no clumping and no more than 1.0% total impurities after storage at ambient conditions.

- 9 041137 (at a temperature of about 25°C and a relative humidity of about 60%) for at least 6 months.

The content of the drug and impurities can be determined using various analytical methods such as HPLC, LC-MS and TLC.

It has been observed that when various nasal pharmaceutical compositions were prepared containing mometasone, an ester or salt thereof, and olopatadine or a salt thereof, such compositions generally showed physical separation in the suspension composition. This physical instability further leads to a lack of dose uniformity. Surprisingly, it has been found that the addition of hydrocolloid at specific concentrations (eg, at a concentration of at least about 0.1% by weight) to the suspension composition provides a physically stable composition (no separation) that is suitable for nasal administration.

In another embodiment, the pharmaceutical composition is a stable, fixed dose, aqueous pharmaceutical suspension composition for nasal administration to a human, wherein the composition contains from about 0.025 to about 0.05% by weight of mometasone, its ester (e.g., mometasone furoate), or its salt and from about 0.6 to about 0.7% by weight of olopatadine or a salt thereof (eg, olopatadine hydrochloride) and a hydrocolloid.

In yet another embodiment of the invention, the pharmaceutical composition is a stable, fixed dose, aqueous pharmaceutical suspension composition for nasal administration to a human, wherein the composition contains from about 0.025 to about 0.05% by weight of mometasone, its ester (e.g., mometasone furoate) or a salt thereof, and about 0.6 to about 0.7% by weight of olopatadine or a salt thereof (eg, olopatadine hydrochloride) and a hydrocolloid that contains sodium carboxymethyl cellulose and xanthan gum. The hydrocolloid may be present at a concentration of at least about 0.1% by weight of the composition.

In yet another embodiment of the invention, the pharmaceutical composition is a stable fixed dose, aqueous pharmaceutical suspension composition for nasal administration to a human, containing from about 0.025 to about 0.05% by weight of mometasone, from about 0.6 to about 0.7% by weight. mass of olopatadine hydrochloride and a hydrocolloid that contains xanthan gum. The xanthan gum may be present at a concentration of at least about 0.1% by weight, or preferably from about 0.3% to about 3% by weight of the composition.

In yet another embodiment of the invention, the pharmaceutical composition is a stable, fixed dose, aqueous pharmaceutical suspension composition for nasal administration to a human, containing from about 0.025 to about 0.05% by weight of mometasone, from about 0.6 to about 0.7% by weight olopatadine hydrochloride and a hydrocolloid that contains sodium carboxymethylcellulose. Sodium carboxymethyl cellulose may be present at a concentration of at least about 0.1% by weight, or preferably from about 0.1 to about 3% by weight of the composition.

In yet another embodiment of the invention, the pharmaceutical composition is a stable, fixed-dose, aqueous pharmaceutical composition in the form of a suspension for nasal administration to humans, containing mometasone, its ester, or a pharmaceutically acceptable salt (e.g., mometasone furoate), olopatadine, or a pharmaceutically acceptable salt thereof ( eg, olopatadine hydrochloride), a hydrocolloid (eg, at a concentration of at least about 0.1% by weight of the composition), and a pharmaceutically acceptable excipient.

One of skill in the art will also appreciate that one or more additional pharmaceutically acceptable excipients may be added as needed to improve the physical properties, appearance or odors of the composition of the present invention. Suitable pharmaceutically acceptable excipients include, but are not limited to, chelating agents, preservatives, buffers, surfactants, isotonic agents, taste-masks, antioxidants, humectants, pH adjusters, and any combination of any of the above.

Suitable surfactants that can be used to form an aqueous nasal spray composition may include one or more anionic, cationic, nonionic, or zwitterionic surfactants. Examples of suitable surfactants that can be used in the aqueous nasal spray suspension can be selected from, but are not limited to, the following: эфир, полиоксиэтиленалкилариловый эфир, полиоксиэтиленмонолаурат, полиоксиэтиленовое растительное масло, полиоксиэтиленсорбитанмонолаурат, полиоксиэтиленовые эфиры или смешанные жирные и смоляные кислоты, производное полиоксиэтиленсорбитланолина, полиоксиэтилентридециловый эфир, полиоксиэтиленсорбитановые сложные эфиры смешанных жирных и смоляных кислот, полиоксиэтиленсорбитанмоностеарат, полиоксиэтиленсорбитанмоноолеат, полиоксиэтиленмоностеарат, полиоксиэтиленстеариловый эфир, полиоксиэтиленовый олеиловый эфир, polyoxyethylene tridecyl ether, polyoxyethylene fatty alcohol, polyoxyethylene alkylamine, monopal polyoxyethylene glycol mitate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene cetyl ether, polyoxyethyleneoxypropylene stearate, polyoxyethylene lauryl ether, polyoxyethylenelanolin derivative, sodium oleate, quaternary ammonium derivative, potassium oleate, N-cetyl N-ethylmorpholinium ethosulfate, sodium lauryl sulfate, or mixtures thereof. Preferred surfactants are polyethoxylated sorbitan derivatives (such as polysorbate 80). The amount of surfactant may vary from about 0.001 to about 1% by weight based on the total weight of the composition.

In order to improve the ability of the nasal spray aqueous suspension to be well tolerated when applied to the nasal mucosa, it is preferable to formulate it as isotonic. The osmolality can be set by changing the amount of substances present in the aqueous nasal spray suspension other than mometasone, olopatadine and any other substances present and/or by adding an isotonic substance, preferably a physiologically acceptable salt such as, for example, sodium chloride or potassium chloride, or a physiologically tolerable polyol, such as, for example, a sugar alcohol, in particular sorbitol or glycerol, at a concentration necessary to obtain isotonicity.

Examples of suitable preservatives that can be used in the aqueous nasal spray suspension include, but are not limited to, benzyl alcohol, quaternary ammonium halides, phenylcarbinol, thimerosal, and disodium edetate. Quaternary ammonium halides are preferred. Suitable quaternary ammonium halides preservatives include polyquaternium-1 and benzalkonium halides. Preferred benzalkonium halides include benzalkonium chloride and benzalkonium bromide. The amount of preservative present in the aqueous nasal spray suspension may vary from about 0.005% to about 0.2% by weight based on the total weight of the composition. Preferably, the preservative is present at a concentration of about 0.02% by weight based on the total weight of the composition.

Examples of suitable chelating agents that can be used in the aqueous nasal spray suspension include, but are not limited to, disodium edetate (EDTA), trisodium edetate, tetrasodium edetate, and diethylamine pentaacetate, preferably EDTA. The amount of chelating agent present in the aqueous nasal spray suspension may vary from about 0.0002 to about 0.5% by weight based on the total weight of the composition.

Examples of suitable buffers that can be used in the aqueous nasal spray suspension include, but are not limited to, citric acid, acetic acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, phosphate salts (eg, dibasic sodium phosphate, such as dibasic sodium 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 from about 3 to about 6. Preferably, the amount of buffer is in the range from about 0.005 to about 1% by weight based on the total weight of the composition.

Examples of suitable sweeteners/taste maskers that can be used in the aqueous nasal spray suspension include, but are not limited to, sucralose, thaumatin, sucrose, saccharin (including salts such as sodium and calcium salts), fructose, glucose, dextrose , corn syrup, aspartame, acesulfame-K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, neotame, mannitol, eucalyptus oil, camphor, and natural or artificial flavors or flavors (e.g., menthol, mint, vanilla, orange, etc. ), or combinations of two or more of these substances. A particularly preferred taste masking agent is sucralose. The amount of sweetener/taste masker present in the aqueous nasal spray suspension may vary from about 0.01 to about 1% by weight based on the total weight of the composition.

Examples of suitable antioxidants that can be used in the aqueous nasal spray suspension include, but are not limited to, ascorbic acid, alpha-tocopherol (vitamin-E), butylated hydroxyanisole, butylated hydroxytoluene, glutathione, and any combination of any of the above. The amount of antioxidants present in the aqueous nasal spray suspension may vary from about 0.0002 to about 0.5% by weight based on the total weight of the composition.

Examples of suitable humectants that can be used in the aqueous nasal spray suspension include, but are not limited to, glycerin, sorbitol, polyethylene glycol, propylene glycol, or mixtures thereof, which are mixed with a suitable humectant such as water. The amount of humectant present in the aqueous nasal spray suspension may vary from about 0.0002 to about 0.5% by weight based on the total weight of the composition.

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

The pharmaceutical composition for nasal administration may have a pH of about 3.3 to about 4.1, or about 3.5 to about 3.9. The inventors have found that olopatadine hydrochloride crystallizes from a fixed dose aqueous suspension combination at pH 5 to 5.5. However, olopatadine hydrochloride remains dissolved in an aqueous suspension at a pH of about 3.3 to about

- 11 041137

4.1.

The aqueous pharmaceutical composition is preferably substantially free of olopatadine hydrochloride crystals. In one embodiment, the aqueous pharmaceutical composition contains less than 2%, less than 1%, less than 0.5%, less than 0.2%, or less than 0.1% crystalline olopatadine hydrochloride, based on 100% of the total weight of olopatadine hydrochloride in the composition. In another embodiment, the aqueous pharmaceutical composition is substantially free of olopatadine hydrochloride crystals after 3 or 6 months of storage at 25±2°C and 60±5% relative humidity, or at 40±2°C and 75%± relative humidity. 5%. In yet another embodiment of the invention, the aqueous pharmaceutical composition contains less than 2%, less than 1%, less than 0.5%, less than 0.2%, or less than 0.1% of crystalline olopatadine hydrochloride, based on 100% of the total weight of olopatadine hydrochloride in the composition, after 3 or 6 months of storage at 25±2°C and 60±5% relative humidity or at 40±2°C and 75%±5% relative humidity.

The osmolality of the composition may range from about 200 to about 400 mOsm/kg, or from about 250 to about 350 mOsm/kg. The viscosity of the composition may vary from about 10 to about 200 centipoise, or preferably from about 20 to about 150 centipoise. Viscosity can be determined by various known instruments such as a dynamic rheometer or a Brookfield viscometer. In a preferred embodiment of the invention, the viscosity is determined using a Brookfield viscometer by measuring the transmission of torque through the sample using a rotating spindle.

In yet another aspect of the invention, the pharmaceutical composition is in the form of a suspension and contains mometasone, an ester thereof, or a salt thereof, preferably mometasone furoate, in particles with an average particle size in the range of about 1 to about 20 microns, or preferably about 1 to about 15 µm. In one aspect of the invention, the suspension pharmaceutical composition has an average particle size of less than 15 microns, as determined using microscopy technology.

In yet another aspect of the invention, the pharmaceutical composition, when delivered in a dispenser, may be in the form of a spray with a longest axis of about 15-75 mm, a shortest axis of about 10-65 mm and an ellipticity of about 1-2.

In yet another embodiment of the invention, the pharmaceutical composition is a stable, fixed dose, aqueous pharmaceutical composition for nasal administration to a human, wherein the composition contains from about 0.001 to about 0.075% by weight mometasone furoate monohydrate and from about 0.5 to about 0.8 % by weight of olopatadine hydrochloride.

In yet another embodiment of the invention, the pharmaceutical composition is a stable pharmaceutical composition in the form of a fixed dose suspension for nasal administration to humans, containing mometasone furoate monohydrate, olopatadine hydrochloride and a hydrocolloid that contains xanthan gum at a concentration of about 0.3% by weight of the composition, when this composition has a pH of from about 3.5 to about 3.9.

In yet another embodiment of the invention, the pharmaceutical composition is a stable pharmaceutical composition in the form of a fixed dose suspension for human nasal administration, containing mometasone furoate monohydrate, olopatadine hydrochloride and a hydrocolloid that contains sodium carboxymethylcellulose at a concentration of about 0.5% by weight of the composition, wherein the composition has a pH of about 3.5 to about 3.9.

In yet another embodiment, the pharmaceutical composition is a fixed dose, stable pharmaceutical aqueous suspension composition for nasal administration to humans, wherein the composition comprises (1) about 0.025% by weight of mometasone furoate monohydrate, (2) about 0.665% by weight of olopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3% by weight xanthan gum and about 0.5% by weight sodium carboxymethyl cellulose, (4) about 0.02% by weight benzalkonium chloride, (5) about 0.4% by weight chloride sodium, (6) about 0.01% by weight of disodium edetate, (7) about 0.94% by weight of sodium phosphate heptahydrate, and (8) about 0.01% by weight of polysorbate 80.

In yet another embodiment, the pharmaceutical composition is a fixed dose, stable pharmaceutical aqueous suspension composition for nasal administration to a human, wherein the composition comprises (1) about 0.050% by weight of mometasone furoate monohydrate, (2) about 0.665% by weight of olopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3% by weight xanthan gum and about 0.5% by weight sodium carboxymethyl cellulose, (4) about 0.02% by weight benzalkonium chloride, (5) about 0.4% by weight chloride sodium, (6) about 0.01% by weight of disodium edetate, (7) about 0.94% by weight of sodium phosphate heptahydrate, and (8) about 0.01% by weight of polysorbate 80.

In yet another embodiment of the invention, the pharmaceutical composition is a stable fixed dose pharmaceutical aqueous suspension composition for nasal administration to a human, wherein the composition contains (1) about 0.025% by weight of mometasone

- 12 041137 furoate monohydrate, (2) about 0.665% by weight of olopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3% by weight of xanthan gum and about 0.5% by weight of sodium carboxymethyl cellulose, (4) from about 1 to about 1.2% by weight of a mixture of microcrystalline cellulose and sodium carboxymethylcellulose, (5) about 0.02% by weight of benzalkonium chloride, (6) about 0.4% by weight of sodium chloride, (7) about 0.01% by weight of disodium edetate, (8) about 0.94% by weight of sodium phosphate heptahydrate, and (9) about 0.01% by weight of polysorbate 80.

In yet another embodiment, the pharmaceutical composition is a fixed dose, stable pharmaceutical aqueous suspension composition for nasal administration to a human, wherein the composition comprises (1) about 0.050% by weight of mometasone furoate monohydrate, (2) about 0.665% by weight of olopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3% by weight of xanthan gum and about 0.5% by weight of sodium carboxymethylcellulose, (4) from about 1 to about 1.2% by weight of a mixture of microcrystalline cellulose and sodium carboxymethylcellulose, (5) about 0.02% by weight benzalkonium chloride, (6) about 0.4% by weight sodium chloride, (7) about 0.01% by weight disodium edetate, (8) about 0.94% by weight sodium phosphate heptahydrate and ( 9) about 0.01% by weight of polysorbate 80.

In yet another embodiment of the invention, the pharmaceutical composition is a stable suspension suitable for nasal administration to humans, containing (a) an aqueous solvent, (b) particles of mometasone furoate suspended in a solvent, wherein the particles have an average particle size of from about 1 to about 20 μm, (c) olopatadine hydrochloride dissolved in a solvent; and (d) a hydrocolloid, the suspension having a viscosity in the range of about 20 to about 150 centipoise. In one preferred embodiment, the suspension has a pH of about 3.5-3.9 and an osmolality in the range of about 250 to about 350 mOsm/kg. In one embodiment, the suspension further comprises a chelating agent, a preservative, a buffer, a surfactant, an isotonic agent, and optionally a pH adjusting agent.

Preferably the slurries have only one phase (ie, they are preferably a single phase slurry).

In a further embodiment of the invention, the dispenser device containing the pharmaceutical composition is provided with a package insert containing instructions for using the pharmaceutical composition.

In a further embodiment of the invention, the pharmaceutical composition, when supplied from a dispenser, may provide a spray pattern with a longest axis of about 1575 mm, a shortest axis of about 10-65 mm, and an ellipticity of about 1-2. Spray pattern can be determined by various known methods such as ADSA with NSPUA (Innova system) and spray droplet size distribution can be determined by various known methods such as Malvern Spraytec with NSPUA (Innova system).

A typical procedure for characterizing a spray droplet size distribution is described below. The atomizer is loaded with the composition described above, and filled with an executive pump by means of a drive until a fine mist appears from the atomizer nozzle. A commercially available laser diffraction tool is designed such that the nozzle is 3 or 6 cm below the laser beam of the laser diffraction tool. The pump is driven by a constant force drive. The resulting spray composition crosses the laser beam. Data is collected for D ₁₀ , D ₅₀ , D ⁹⁰ , SPAN and % volume <10 µm. Average values are calculated for each of these parameters for three sprays.

The pharmaceutical composition may be administered via a dosing device for the treatment of rhinitis. In one embodiment, each spray provides (i) mometasone furoate monohydrate equivalent to about 25 micrograms of mometasone furoate, and (ii) olopatadine hydrochloride equivalent to about 600 micrograms of oxypatadine (e.g., 665 micrograms of oxypatadine hydrochloride). In one preferred embodiment of the invention, a person suffering from allergic rhinitis is administered two sprays of the pharmaceutical composition from a dosing device twice a day. In another embodiment, a person suffering from allergic rhinitis is nasally injected with 100 μg of mometasone furoate and 1330 μg of olopatadine hydrochloride twice daily using a dosing device. In yet another embodiment of the invention, a person suffering from allergic rhinitis is nasally administered with 200 μg of mometasone furoate and 2660 μg of olopatadine hydrochloride daily using a dosing device. Rhinitis includes, but is not limited to, irritation and inflammation of the mucous membrane inside the nose and associated nasal and non-nasal symptoms. It includes allergic rhinitis, persistent rhinitis, perennial rhinitis, seasonal rhinitis, chronic rhinitis, drug rhinitis, vasomotor rhinitis, infectious rhinitis, autonomic rhinitis, hormonal rhinitis, drug rhinitis, atrophic rhinitis and gustatory rhinitis. It preferably includes allergic rhinitis, perennial rhinitis, persistent rhinitis, seasonal rhinitis and related nasal and non-nasal symptoms.

Nasal and non-nasal symptoms associated with allergic rhinitis include sneezing, nasal itching, rhinorrhea (runny nose), nasal obstruction, cough, ocular itching, excessive tear flow, headache, fatigue, colds (also known as nasopharyngitis, nasopharyngitis, acute rhinitis or SARS), malaise and cognitive impairment.

The pharmaceutical composition may contain one or more additional pharmaceutical active substance(s) selected from, but not limited to, the therapeutic category, non-steroidal anti-inflammatory agents, decongestants, and any combination of any of the above.

In one aspect of the invention, the pharmaceutical composition contains from about 0.001 to about 0.075% by weight of mometasone, its ester (e.g., mometasone furoate), or a particulate salt thereof, and from about 0.5 to about 0.8% by weight of olopatadine or its salts (for example, olopatadine hydrochloride) in dissolved form. In this aspect of the invention, the composition may further comprise a hydrocolloid system, for example in an amount sufficient to inhibit phase separation for at least 24 hours when stored at 25±2° C. and 60±5% relative humidity. In one embodiment of the invention, the composition, when stored for 12 months at 25±2°C and 60%±5% relative humidity in a dispenser, has one or more of the following properties:

(i) the composition contains no more than 1% of the total amount of impurities (after storage);

(ii) the composition contains no more than 1% DMC (after storage);

(iii) the composition contains no more than 1% DMCF (after storage);

(iv) the composition contains no more than 1% α-hydroxyolopatadine (after storage);

(v) the composition contains no more than 1% of the E-isomer of olopatadine (after storage);

(vi) the composition contains no more than 1% olopatadine-bound Compound B (after storage); and/or (vii) the composition contains no more than 0.42% other impurities of olopatadine (after storage).

Methods of treatment

The inventors have also surprisingly found that nasal administration of a pharmaceutical composition of mometasone, its ester (for example, mometasone furoate) or its salt, and olopatadine or its salt (such as olopatadine hydrochloride) provides a faster onset of action in terms of reducing the symptoms associated with allergic rhinitis, such as seasonal allergic rhinitis or perennial allergic rhinitis compared to olopatadine hydrochloride monotherapy or mometasone furoate monotherapy. In particular, the pharmaceutical composition provides more rapid relief of nasal symptoms such as nasal congestion, rhinorrhea, itching and sneezing. The pharmaceutical composition may also provide a faster onset of action with respect to ocular symptoms such as ocular itching, lacrimation/watery eyes, and redness of the eyes. The onset of action may be less than 30 minutes, such as within about 15 minutes, such as within about 10 minutes. One embodiment of the invention is a method of treating allergic rhinitis in a patient (e.g. human) in need thereof, comprising nasally administering to the patient an effective amount of a fixed dose pharmaceutical composition, e.g. from a dispenser described above, wherein the pharmaceutical composition contains mometasone, its ester or its salt; and olopatadine or its salt. Preferably, the composition is administered nasally as 1 or 2 sprays per nostril of the patient at least once a day. Each spray preferably contains mometasone, its ester or salt thereof, and olopatadine or its salt in a weight ratio of from about 1:5 to about 1:60, for example, in a weight ratio of from about 1:12 to about 1:53, from about 1:13.3 to about 1:50, or about 1:18 to about 1:40 (based on the equivalent weight of pure olopatadine). In one specific embodiment of the invention, the fixed dose pharmaceutical composition is a suspension in which mometasone, its ester or salt is present in particulate form and olopatadine or its salt is present in dissolved form.

Another embodiment of the invention is a method of providing a more rapid onset of relief of symptoms associated with allergic rhinitis in a person in need, comprising nasal administration twice a day, two sprays per nostril, a fixed dose pharmaceutical composition, for example, from the above-described dosing device, in which the pharmaceutical composition contains mometasone, its ester or its salt (for example, mometasone furoate), and olopatadine, its salt (for example, olopatadine hydrochloride). This method can provide a more rapid onset of reduction of one or more symptoms compared with the administration of mometasone, its ester or its salt in monotherapy, or olopatadine or its salt in monotherapy. Each spray may contain mometasone, an ester thereof, or a salt thereof, and olopatadine, or a salt thereof, in a weight ratio of from about 1:5 to about 1:60 (e.g., a weight ratio of about 1:12 to about 1:53, from about 1 :13.3 to about 1:50 or about 1:18 to about 1:40) (based on the equivalent weight of pure olopatadine) (e.g., each spray contains about 12.5 micrograms, about 25 micrograms, about 37.5 mcg, about 50 mcg or about 62.5 mcg of mometasone, its ester or salt thereof (for example, about 50 mcg of mometasone furoate) and olopatadine hydrochloride, equivalent to about 300 mcg, about 450 mcg, about

- 14 041137

600 micrograms, about 750 micrograms, or about 900 micrograms of olopatadine (for example, about 665 micrograms of olopatadine hydrochloride)). Administration may provide relief from one or more symptoms within 30 minutes, such as within 15 or 10 minutes. In another embodiment, the administration may provide relief from one or more symptoms of allergic rhinitis (such as nasal symptoms) in a patient exposed to an environmental exposure chamber (EEC) (such as ragweed pollen at a concentration of 3500 ± 500 particles/m ³ in within 6 hours) less than 15 minutes, for example within about 10 minutes.

In one embodiment, the methods herein provide a faster onset of action to relieve nasal symptoms in a patient. In another embodiment, the methods herein provide a faster onset of action to relieve ocular symptoms in a patient.

In one embodiment of the invention, the pharmaceutical composition provides a faster onset of action to relieve nasal symptoms in a patient. In yet another embodiment of the invention, the pharmaceutical composition provides a faster onset of action to relieve eye symptoms in a patient.

Another embodiment of the invention is a method of treating a person suffering from allergic rhinitis, comprising the step of administering to the patient a pharmaceutical composition in the form of nasal administration twice a day of two sprays per nostril, for example, from a dosing device described above, wherein (i) the pharmaceutical composition provides an onset action for 15 minutes for the treatment of allergic rhinitis and (ii) each spray of the pharmaceutical composition contains about 25 μg of mometasone furoate and about 665 μg of olopatadine hydrochloride.

Another embodiment is a method of treating a human suffering from allergic rhinitis, comprising the steps of:

(a) administering to a patient (e.g., a human) a fixed-dose pharmaceutical composition for nasal administration twice daily, two sprays per nostril, optionally in combination with a dosing device as described above, wherein the fixed-dose pharmaceutical composition comprises mometasone, an ester thereof, or its salt (for example, mometasone furoate) and olopatadine or its salt (for example, olopatadine hydrochloride), and each spray contains mometasone, its ester or its salt, and olopatadine or its salt in a weight ratio of from about 1:5 to about 1 :60 (for example, a weight ratio of about 1:12 to about 1:53, about 1:13.3 to about 1:50, or about 1:18 to about 1:40) (based on the equivalent weight of pure olopatadine ) (for example, each spray contains about 12.5 micrograms, about 25 micrograms, about 37.5 micrograms, about 50 micrograms, or about 62.5 micrograms of mometasone, its ester, or its salt (for example, about 50 micrograms of mometasone furoate) and olopatadine hydrochloride, equivalent to about 300 m kg, about 450 micrograms, about 600 micrograms, about 750 micrograms, or about 900 micrograms of olopatadine (e.g., about 665 micrograms of olopatadine hydrochloride)), administered according to (i) the marketing of the pharmaceutical composition, optionally in combination with a dosing device, described above as (A), providing a faster onset of action (e.g., onset of action within less than 30 minutes, e.g., within 15 minutes, e.g., within 10 minutes) to alleviate one or more symptoms (e.g., nasal symptoms) of an allergic rhinitis than nasal administration of mometasone, its ester or salt (eg, 25 or 50 mcg mometasone furoate) or olopatadine or its salt (eg, 665 mcg olopatadine hydrochloride) alone, (B) providing relief from one or more symptoms of allergic rhinitis within 15 minutes (or 30 minutes), (C) providing a faster onset of action (e.g., within 15 minutes, e.g., within about 10 minutes) to facilitate one or more symptoms (eg, nasal symptoms) of allergic rhinitis in patients exposed in an environmental exposure chamber (EEC) (eg, ragweed pollen at a concentration of 3500 ± 500 particles/m ³ for 6 hours) than nasal administration of mometasone, its an ester or salt thereof, or olopatadine alone or a salt thereof as monotherapy, and/or (D) providing relief from one or more symptoms of allergic rhinitis (eg, nasal symptoms) in patients exposed to an environmental exposure chamber (EEC) ( for example, ragweed pollen at a concentration of 3500±500 particles/m ³ for 6 hours) for 15 minutes, for example for about 10 minutes and (ii) diagnosing a patient suffering from allergic rhinitis; and (b) administering the designated pharmaceutical composition to the patient, optionally using a dosing device as described above. In one preferred embodiment of the invention, each fixed dose pharmaceutical composition spray provides 25 μg of mometasone furoate and 665 μg of olopatadine hydrochloride.

Another embodiment of the invention is a method of treating a human suffering from allergic rhinitis (e.g., seasonal allergic rhinitis or perennial allergic rhinitis) comprising the step of administering to the patient a fixed dose nasal fixed dose pharmaceutical composition twice a day, two sprays per nostril, optionally using the above-described dosing device, while the pharmaceutical composition with

- 15 041137 fixed dose contains mometasone, its ester or its salt (for example, mometasone furoate) and olopatadine or its salt (for example, olopatadine hydrochloride), and each spray contains mometasone, its ester or its salt, and olopatadine or its salt in a weight ratio of about 1:5 to about 1:60 (e.g., a weight ratio of about 1:12 to about 1:53, about 1:13.3 to about 1:50, or about 1:18 to about 1:40) (based on the equivalent weight of pure olopatadine) (for example, each spray contains about 12.5 micrograms, about 25 micrograms, about 37.5 micrograms, about 50 micrograms, or about 62.5 micrograms of mometasone, its ester, or its salts (eg, about 50 µg of mometasone furoate) and olopatadine hydrochloride, equivalent to about 300 µg, about 450 µg, about 600 µg, about 750 µg, or about 900 µg of olopatadine (eg, about 665 µg of olopatadine hydrochloride)). The pharmaceutical composition is administered in accordance with (a) the marketing of the pharmaceutical composition, optionally using the dispensing device described above as (A), providing a faster onset of action (e.g., onset of action within less than 30 minutes, e.g., within 15 minutes, e.g. for 10 minutes) to relieve symptoms (eg, nasal symptoms) of allergic rhinitis than nasal administration of mometasone, its ester or salt (eg, 50 µg mometasone furoate) or olopatadine or its salt (eg, 665 µg olopatadine hydrochloride) in monotherapy, (B) providing relief from one or more symptoms of allergic rhinitis within 15 minutes (or 30 minutes), and (b) diagnosing a patient suffering from allergic rhinitis. In one preferred embodiment of the invention, each fixed dose pharmaceutical composition spray provides 25 μg of mometasone furoate and 665 μg of olopatadine hydrochloride.

Administration of a pharmaceutical composition, e.g., using a dosing device as described above, can provide relief from one or more symptoms of allergic rhinitis (e.g., nasal symptoms or eye symptoms) to a patient faster (e.g., onset of action in less than 30 minutes, e.g., within about 15 minutes). min, for example within 10 min) than nasal administration of mometasone, its ester or its salt, or olopatadine or its salt, in monotherapy. In another embodiment, the administration may provide relief from one or more symptoms of allergic rhinitis (such as nasal symptoms) in a patient exposed to an environmental exposure chamber (EEC) (such as ragweed pollen at a concentration of 3500 ± 500 particles/m ³ in within 6 hours) faster (eg onset of action in less than 15 minutes, eg within about 10 minutes) than nasal administration of mometasone, its ester or salt, or olopatadine or its salt, alone.

Another embodiment of the invention is a method of providing a more rapid onset of relief of symptoms associated with allergic rhinitis in a person in need, comprising nasal administration twice a day, two sprays per nostril, a fixed dose pharmaceutical composition, for example, with using the dosing device described above, wherein the pharmaceutical composition contains mometasone, its ester or salt (for example, mometasone furoate), and olopatadine, its salt (for example, olopatadine hydrochloride). This method can provide a more rapid onset of reduction of one or more symptoms compared with the administration of mometasone, its ester or its salt in monotherapy, or olopatadine or its salt in monotherapy. Each spray may contain mometasone, an ester thereof, or a salt thereof, and olopatadine, or a salt thereof, in a weight ratio of from about 1:5 to about 1:60 (e.g., a weight ratio of about 1:12 to about 1:53, from about 1 :13.3 to about 1:50 or about 1:18 to about 1:40) (based on the equivalent weight of pure olopatadine) (e.g., each spray contains about 12.5 micrograms, about 25 micrograms, about 37.5 mcg, about 50 mcg or about 62.5 mcg of mometasone, its ester or salt thereof (e.g., about 50 mcg of mometasone furoate) and olopatadine hydrochloride, equivalent to about 300 mcg, about 450 mcg, about 600 mcg, about 750 mcg or about 900 micrograms of olopatadine (for example, about 665 micrograms of olopatadine hydrochloride)). Administration may provide relief of one or more symptoms within 30 minutes, such as within 15 minutes or within 10 minutes. In another embodiment, the administration may provide relief from one or more symptoms of allergic rhinitis (such as nasal symptoms) in a patient exposed to an environmental exposure chamber (EEC) (such as ragweed pollen at a concentration of 3500 ± 500 particles/m ³ in within 6 hours) less than 15 minutes, for example within about 10 minutes.

Another embodiment of the invention is a method of treating a human suffering from allergic rhinitis, comprising the step of administering to the patient a pharmaceutical composition in the form of nasal administration twice a day of two sprays per nostril, for example, using a dosing device described above, wherein (i) the pharmaceutical composition provides onset of action within 15 minutes for the treatment of allergic rhinitis; and (ii) each spray of the pharmaceutical composition contains about 25 μg of mometasone furoate and about 665 μg of olopatadine hydrochloride.

In one embodiment, according to any of the methods described herein, the allergic rhinitis is selected from the group consisting of perennial allergic rhinitis, persistent allergic rhinitis, seasonal allergic rhinitis, and associated nasal and/or non-nasal symptoms. In one preferred embodiment of the invention,

- 16 041137 according to any of the methods described herein, allergic rhinitis is seasonal allergic rhinitis. In another preferred embodiment of the invention according to any of the methods described herein, the allergic rhinitis is perennial allergic rhinitis.

It should be understood that various modifications may be made to the embodiments of the invention described herein. For this reason, the above description should not be considered as limiting, but merely as illustrative examples of preferred embodiments of the invention. Other designs and methods may be implemented by those skilled in the art without departing from the scope and spirit of the present invention.

The following examples are provided to enable those skilled in the art to practice the invention and are merely illustrative of the present invention. These examples are not to be construed as limiting the scope of the present invention.

Examples

Examples 1 and 2.

Suspension compositions containing mometasone furoate, olopatadine hydrochloride and sodium carboxymethylcellulose

Serial number Ingredient Example 1 (in percent by weight) Example 2 (in percent by weight) 1 Mometasone furoate monohydrate equivalent to mometasone furoate 0.050 0.025 2 Olopatadine hydrochloride 0.665 0.665 3 Avicel RC 591 (microcrystalline cellulose and sodium carboxymethyl cellulose) 1,200 1,200 4 Benzalkonium chloride (50% solution) 0.040 0.040 5 Sodium carboxymethyl cellulose (Cekol 2000 R) 0.500 0.500 6 Sodium chloride 0.410 0.410 7 Disodium edetat 0.010 0.010 8 Dibasic sodium phosphate heptahydrate 0.940 0.940 9 Polysorbate 80 0.010 0.010 10 Sodium hydroxide V enough V enough AND Hydrochloric acid V enough V enough 12 Water for injections V enough V enough Research results Physical observation while standing for 24 hours Phase separation was not observed Phase separation was not observed Average particle size by microscopy Below 15 µm. Below 15 µm.

Manufacturing procedure:

1. Avicel RC-591 was added to water for injection with homogenization and left to hydrate.

2. Sodium carboxymethyl cellulose 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.

4. Step 3 was added to step 1 with homogenization.

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

6. Step 5 was added to step 4 with homogenization.

7. Benzalkonium chloride was dissolved in water for injection.

8. Step 7 was added to step 6 with homogenization.

9. The pH was checked and adjusted to 3.5-3.9 with HCl and the total weight was adjusted with water for injection. The osmolality of the composition was about 250-350 mOsm/kg. The composition was subjected to stability studies under various conditions.

The results of the above are as follows:

Container details: Atomizer containing a HDPE vial crimped by a pump and provided with an actuator and a cap.

Stability study data Study Primary 3 months 6 months Example 1 Example 2 Example 1 Example 2 Example 1 Example 2 Stability (25°C ± 2°C and 60% ± 5% RH) pH 3.61 3.69 3.73 3.78 3.81 Osmolality (mOsm)* 310 308 299 298 302 311 Viscosity (cP)** 32.5 42.5 42.3 40.6 40.9 Weight per ml (g/ml) 1.01 1.021 1.024 1.029 1.019 Mometasone furoate assay (% by mass) 101 102.4 99.1 99.3 98.2 97.2 Analysis of olopatadine hydrochloride (% by mass) 98.2 99.9 97.3 99.1 97.8 97.9 Related substances for mometasone furoate

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Impurity DMCF (%) 0.02 0.03 0.09 0.10 0.14 0.17 Any other impurity (%) 0.04 0.04 0.03 Total impurity content (%) 0.09 0.23 0.29 0.31 0.34 Related substances for olopatadine hydrochloride Olopatadine Eisomer (%) 0.08 0.07 0.09 0.09 Any other impurity (%) 0.03 0.04 0.09 0.12 oh and oh and Total impurity content (%) 0.15 0.16 0.20 0.25 0.37 0.38 Spray pattern (per 6 cm) Main axis (mm) 52 60 63 59 61 Minor axis (mm) 43 47 49 53 49 51 Ellipticity 1.2 1D 1.1 1.2 1.1 1.2 Droplet size distribution (per 6 cm) D ίο (µm) 18.91 19.45 19.26 19.70 19.33 18.88 Dso (µm) 36.39 37.61 35.96 37.34 39.28 37.85 D 90 (µm) 72.46 76.44 70.29 75.78 85.42 72.07 SPAN 1.47 1.51 1.42 1.5 1.67 1.46 Stability (40°C ± 2°C and 75% ± 5% RH) pH 3.61 3.68 3.72 3.59 3.68 Osmolality (mOsm) 310 308 298 306 305 299

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Viscosity (cP) 32.5 45.2 42.6 41.8 41.5 Weight per ml (g/ml) 1.01 1.023 1.019 1.026 1.025 Mometasone furoate assay (%) 101 102.4 99.8 100.4 98.3 98.4 Analysis of olopatadine hydrochloride (%) 98.2 99.9 99.3 102.5 98.7 99.7 Related substances for mometasone furoate Impurity DMCF (%) 0.02 0.03 0.014 0.20 0.25 0.25 Any other impurity (%) 0.04 0.04 0.04 0.03 0.03 0.04 Total impurity content (%) 0.09 0.25 0.39 0.40 0.46 Related substances for olopatadine hydrochloride Olopatadine Eisomer (%) 0.08 0.07 0.08 0.08 0.09 Any other impurity (%) 0.03 0.04 0.21 0.18 0.31 0.30 Total impurity content (%) 0.15 0.16 0.32 0.36 0.68 0.64 Spray pattern (per bcm) Main axis (mm) 52 52 61 58 58 58 Minor axis (mm) 43 47 50 49 48 49 Ellipticity 1.2 1.1 1.2 1.2 1.2 1.2 Droplet size distribution (per 6 cm) D u (µm) 18.91 19.45 19.49 19.27 18.05 18.09 Dso (µm) 36.39 37.61 35.29 34.68 36.19 36.12 D 90 (µm) 72.46 76.44 64.66 63.49 71.89 70.06 SPAN 1.47 1.51 1.28 1.27 1.50 1.44

* Determined by Advanced Instruments Osmometer (Model 3250).

** Determined using a Brookfield viscometer.

Examples 3 and 4.

Suspension compositions containing mometasone furoate, olopatadine hydrochloride and xanthan gum

Serial number Ingredient Example 3 (in percent by weight) Example 4 (in percent by weight) 1 Mometasone furoate monohydrate equivalent to mometasone furoate 0.050 0.025 2 Olopatadine hydrochloride 0.665 0.665 3 Avicel RC 591 (microcrystalline cellulose and sodium carboxymethyl cellulose) 1,000 1,000 4 Benzalkonium chloride (50% solution) 0.040 0.040

- 20 041137

5 Xantural 75 (xanthan gum) 0.300 0.300 6 Sodium chloride 0.410 0.410 7 Disodium edetat 0.010 0.010 8 Dibasic sodium phosphate heptahydrate 0.940 0.940 9 Polysorbate 80 0.010 0.010 10 Sodium hydroxide in sufficient quantity in sufficient quantity AND Hydrochloric acid in sufficient quantity in sufficient quantity 12 Water for injections in sufficient quantity in sufficient quantity Research results Physical observation while standing for 24 hours Phase separation was not observed Phase separation was not observed Average particle size by microscopy Below 15 µm. Below 15 µm.

Manufacturing procedure:

1. Avicel RC-591 was added to water for injection with homogenization and left to hydrate.

2. 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.

4. Step 3 was added to step 1.

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

6. Step 5 was added to step 4 with homogenization.

7. Benzalkonium chloride was dissolved in water for injection.

8. Step 7 was added to step 6 with homogenization.

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

The composition was subjected to stability studies under various conditions. The results of the above are as follows:

Container details: Atomizer containing a HDPE vial crimped by a pump and provided with an actuator and a cap.

Stability study data Study Primary 3 months 6 months Example 3 Example 4 Example 3 Example 4 Example 3 Example 4 Stability (25°C ± 2°C and 60% ± 5% RH) pH 3.65 3.67 3.78 3.65 3.70 3.62 Osmolality (mOsm) 307 312 302 316 308 308 Viscosity (cP) 124.2 129.1 127.9 129.9 126.2 126.8 Weight per ml (g/ml) 1.019 1.022 1.02 1.023 1.02 1.019 Mometasone furoate analysis (%) 99.9 102.8 102.2 99.9 98.7 100.4 Analysis of olopatadine hydrochloride (%) 99.2 100.7 99.7 99.7 99.4 99.6 Related substances for mometasone furoate admixture DMCF (%) 0.02 0.03 0.04 0.05 0.03 0.05

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Any other impurity (%) 0.03 0.04 0.03 0.04 Total impurity content (%) oh and 0.10 0.15 0.16 0.12 0.16 Related Substances for Olopatadine Hydochlooid. 1 Olopatadine Eisomer (%) 0.08 0.07 0.09 oh and oh and 0.10 Any other impurity (%) 0.03 0.04 0.05 0.05 0.08 0.08 Total impurity content (%) 0.18 0.15 0.24 0.20 0.33 0.33 Spray pattern (per 6 cm) Main axis (mm) 46 59 59 56 54 Minor axis (mm) 38 47 44 35 43 Ellipticity 1.2 1.3 1.4 1.6 1.3 Droplet size distribution (per 6 cm) D u (µm) 21.58 21.03 20.95 20.27 18.73 18.34 Dso (µm) 40.44 39.79 37.86 37.93 36.66 36.16 D 90 (µm) 78.25 77.55 74.07 74.93 70.63 70.99 SPAN 1.40 1.42 1.40 1.44 1.40 1.45 Stability (40°C ± 2°C and 75% ± 5% RH) pH 3.65 3.67 3.70 3.77 3.78 3.65 Osmolality (mOsm) 307 312 309 305 302 316 Viscosity (cP) 124.2 129.1 129.6 124.3 127.9 129.9

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Weight per ml (g/ml) 1.05 1.022 1.017 1.027 1.022 1.020 Mometasone furoate assay (%) 99.9 102.8 101.7 100.6 99.6 98.4 Analysis of olopatadine hydrochloride (%) 99.2 100.7 101.7 99.4 99.7 99.9 Related substances for mometasone furoate admixture DMCF (%) 0.02 0.02 0.010 0.12 0.10 0.12 Any other impurity (%) 0.03 0.03 0.02 0.03 0.05 0.03 Total impurity content (%) 0.011 0.10 0.20 0.22 0.18 0.21 Related substances for olopatadine hydrochloride Olopatadine Eisomer (%) 0.08 0.07 0.12 0.13 oh and oh and Any other impurity (%) 0.03 0.04 0.06 0.06 0.12 0.12 General impurity content (%) 0.18 0.15 0.26 0.26 0.18 0.21 Spray pattern (per bcm) Main axis (mm) 46 46 56 58 54 55 Minor axis (mm) 38 38 45 49 34 43 Ellipticity 1.2 1.2 1.3 1.2 1.3 1.6 Droplet size distribution (per b cm) D ίο (µm) 21.58 21.03 20.67 23.16 19.13 19.16 Dso (µm) 40.44 39.79 38.06 39.08 37.34 37.26 D 90 (µm) 78.25 77.55 75.63 69.37 72.36 72.49 SPAN 1.40 1.42 1.44 1.19 1.42 1.43

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Comparative examples A and B.

Suspension composition containing mometasone furoate and olopatadine hydrochloride

Serial number Ingredient (in percent by mass) A IN 1 Mometasone furoate monohydrate equivalent to mometasone furoate 0.050 0.050 2 Olopatadine hydrochloride 0.665 0.665 3 Avicel RC 591 (microcrystalline cellulose and sodium carboxymethyl cellulose) 1.00 1.00 4 Benzalkonium chloride (50% solution) 0.040 0.040 5 Sodium- carboxymethyl cellulose (Cekol 2000 R) 0.00 0.150 6 Sodium chloride 0.410 0.410 7 Disodium edetat 0.010 0.010 8 Dibasic sodium phosphate heptahydrate 0.940 0.940 9 Polysorbate 80 0.010 0.010 10 Sodium hydroxide V enough V enough AND Hydrochloric acid V enough V enough 12 Water for injections V enough V enough Research results pH 3.7 3.7 Physical observation while standing for 24 hours Phase separation is observed Phase separation is observed

Manufacturing procedure:

The manufacturing procedure as described in example 1 was used.

Comparative Examples C and D.

Suspension composition containing mometasone furoate and olopatadine hydrochloride

Sequence number R Ingredient (in percent by mass) WITH D 1 Mometasone furoate monohydrate equivalent to mometasone furoate 0.050 0.050 2 Olopatadine hydrochloride 0.665 0.665

- 24 041137

3 Avicel RC 591 (microcrystalline cellulose and sodium carboxymethyl cellulose) 1,000 1,000 4 Benzalkonium chloride (50% solution) 0.040 0.040 5 Xantural 75 (xanthan gum) 0.00 0.20 6 Sodium chloride 0.410 0.410 7 Disodium edetat 0.010 0.010 8 Dibasic sodium phosphate heptahydrate 0.940 0.940 9 Polysorbate 80 0.010 0.010 10 Sodium hydroxide in sufficient quantity in sufficient quantity AND Hydrochloric acid in sufficient quantity in sufficient quantity 12 Water for injections in sufficient quantity in sufficient quantity Research results pH 3.73 3.70 Physical observation while standing for 24 hours Phase separation observed Phase separation is observed

Manufacturing procedure:

The fabrication procedure was as described in Example 3.

Example 5 Clinical Study of a Fixed Dose Combination of Mometasone and Olopatadine Nasal Spray in Patients

The study was a single-center, double-blind, double-blind, randomized, parallel-group, comparative study using an Environmental Exposure Chamber (EEC) to evaluate the efficacy, safety, and tolerability of (i) a two-drug combination of a fixed dose of mometasone furoate and olopatadine hydrochloride nasal spray (ii) fixed dose combination of azelastine hydrochloride and fluticasone propionate nasal spray (DYMISTA®), (iii) olopatadine nasal spray (PATANASE®), and (iv) placebo nasal spray in patients with seasonal allergic rhinitis (SAR).

Basic goals

Evaluation of the efficacy of two doses of the fixed dose combination (FDC) of mometasone furoate and olopatadine hydrochloride nasal spray versus placebo nasal spray.

Evaluation of the comparative efficacy of (i) two fixed-dose regimens containing mometasone furoate and olopatadine hydrochloride nasal spray, (ii) a fixed-dose combination of azelastine hydrochloride and fluticasone propionate nasal spray (DYMISTA®), and (iii) olopatadine nasal spray (PATANASE®).

Comparison of the efficacy of (i) fixed dose combination of azelastine hydrochloride and fluticasone propionate nasal spray and (ii) olopatadine nasal spray versus placebo nasal spray.

To compare the onset of action between main groups after the first dose, defined as the first time point after the start of treatment, when the drug shows a significant reduction in the current TNSS score compared to placebo treatment, which proves resistance from this point.

To compare the Quality of Life Questionnaire (QoLQ) and tolerability and acceptability between a fixed-dose combination of mometasone furoate and olopatadine hydrochloride once daily and a fixed-dose combination of mometasone furoate and olopatadine hydrochloride twice daily.

Assess comparative safety between different treatment option groups.

Sample size

The study randomized 36 patients per treatment group. The total number of randomized patients in the five treatment groups was 180.

Patient population

The study included patients suffering from seasonal allergic rhinitis within the past two years who require treatment with either intranasal antihistamines or intranasal steroids.

Key Patient Selection Criteria

1. Age of patients >18 and <65 years, including both sexes;

2. Patient with a known history of seasonal allergic rhinitis (at least 2 years) and demonstrating a positive skin prick test (allergic papule diameter at least 3 mm larger than saline control) for one of the regional allergens;

3. Patients with the ability to understand and sign the written informed consent form that should have been obtained prior to screening; and

4. Patients who wish to comply with the requirements of the protocol.

Study Design

Patients were randomized to treatment in a 1:1:1:1:1 ratio in the following five treatment option groups at one study center:

1. Fixed dose combination of olopatadine hydrochloride 665 mcg and mometasone furoate 25 mcg twice daily (BID)

2. Fixed dose combination of olopatadine hydrochloride 665 mcg and mometasone furoate 50 mcg once daily (QD)

3. DYMISTA® nasal spray (azelastine hydrochloride 137 mcg + fluticasone propionate 50 mcg) twice daily spray (BID)

4. PATANASE® nasal spray (olopatadine hydrochloride 665 mcg) twice daily (BID)

5. Placebo nasal spray

For this study, a double masked design was used, including four masked nasal spray bottles (two for evening dosing and two for morning dosing) (see Table A).

Table A. Treatment with four masked nasal spray bottles

Group by treatment option Morning Evening 1st vial 2nd vial 1st vial 2nd vial 1 TR-1: Fixed dose combination of mometasone furoate 25 mcg + olopatadine hydrochloride 665 mcg twice daily (VS) Active substance Active substance Active substance Active substance

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2 TR-2: Fixed dose combination mometasone furoate 50 mcg + olopatadine hydrochloride 665 mcg once daily (QD) Active substance Active substance placebo placebo 3 DYMISTA® twice a day (VS) placebo Active substance placebo Active substance 4 PATANASE® twice a day (TS) Active substance Active substance Active substance Active substance 5 placebo placebo placebo placebo placebo

This study consisted of five study site visits and a 12-day dosing period at home (and 2 days of on-site dosing for a total of 14 days of dosing). Efficacy endpoints were assessed off-season, at an environmental exposure chamber (EEC) facility. After the first screening visit (Visit 1), patients who met all study criteria (including the main criteria for inclusion: a positive skin prick test (SPT) and a 2-year history of allergic rhinitis (AR) for ragweed allergen) underwent further screening/training at EEC (Environmental Exposure Chamber) (visit 2). During the EEC session, patients were exposed to ragweed pollen at a concentration of 3500±500 particles/m ³ for 6 h. an appropriate TNSS score of 6/12, including a score of at least 2 for nasal congestion on two consecutive diary entries that continued in the study. At visit 3 the following day (day 1), patients who met the minimum criteria returned to the EEC for a second consecutive session at the EEC. Patients were exposed to the allergen for about 10 hours during this visit. During the first 6 h, patients used the electronic diary to complete the symptom assessment every 30 min and performed the minimum appropriate symptom assessment in order to continue. Those who performed the minimum appropriate symptom assessment were randomized to receive one of the five study drugs after the 6 hour time point in the EEC. Following dosing (at approximately noon), patients were asked to undergo a symptom assessment at 5, 10, 15, 25, 30, 45, 60 minutes, and then every 30 minutes for the remainder of the visit. Post-treatment symptom scores in the EEC were used to determine the onset of action for study treatments. Patients were then sent home with their study medications to continue dosing BID (twice daily) at home, starting with the evening dose on Day 1. Patients continued home dosing for 12 days. After 12 days (days 2-13) at home, patients returned to the EEC on day 14 (Visit 4) for a 6-hour post-treatment EEC session. Patients were administered the morning dose of study drug one hour prior to entry into the EEC. Patients in the EEC were assessed for symptoms every 30 min. On the same day, patients took their last dose of study treatment at midnight and returned the following morning (day 15, visit 5) for a 6-hour session at the EEC. For 6 h, patients used an electronic diary to complete symptom assessment every 30 min. In addition to collecting nasal and ocular symptoms, an electronic diary was used to collect the EEC-Quality-of-Life Questionnaire (EEC-QoLQ) using an environmental camera at Visits 2, 3, 4, and 5, and scores acceptability and tolerability at Visit 5. Visit 5 was the final study visit.

Primary processing

Meeting the following criteria at each of two consecutive patient diary readings at the initial visit: a minimum TNSS score of 6 out of 12, including a score of at least 2 for nasal congestion.

Randomization

Patients who met the same criteria on both initial chamber visits of 3 hours in order to progress to the in-treatment visit (Visit 3).

At the treatment visit (Visit 3), the minimum TNSS score is 6 out of 12 (including a score of at least 2 for nasal congestion).

Composition of medicines

The compositions of the study drugs used in the study were as follows: Study drug 1 (TP-1)

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Mometasone furoate monohydrate and olopatadine hydrochloride nasal spray (25 mcg +

600 mcg)

Each spray delivers mometasone furoate monohydrate, the equivalent of 25 micrograms of mometasone furoate, and olopatadine hydrochloride, the equivalent of 600 micrograms of olopatadine.

Investigational drug 2 (TR-2)

Mometasone furoate monohydrate and olopatadine hydrochloride nasal spray (50 mcg + 600 mcg)

Each spray delivers mometasone furoate monohydrate, the equivalent of 50 micrograms of mometasone furoate, and olopatadine hydrochloride, the equivalent of 600 micrograms of olopatadine.

Dosing regimen

1. Investigational drugs

TP-1: Fixed dose combination of olopatadine hydrochloride (665 µg) and mometasone furoate (25 µg) nasal spray: 2 sprays per nostril were administered twice a day (BID) for two weeks.

TP-2: Fixed dose combination of olopatadine hydrochloride (665 µg) and mometasone furoate (50 µg) nasal spray: 2 sprays per nostril administered once daily (QD) for two weeks

2. Comparator drugs

Nasal spray containing olopatadine hydrochloride (PATANASE® 0.6%): 2 sprays per nostril were administered twice a day for two weeks.

DYMISTA® nasal spray (azelastine hydrochloride + fluticasone propionate) 137 mcg/50 mcg: 1 spray per nostril was administered twice a day for two weeks.

Placebo nasal spray (based on study drug excipient): 2 sprays per nostril were administered twice daily for two weeks.

Key Evaluation Criteria (Clinical Endpoints)

Change from entry into the study in mean post-treatment rhinitis symptom score (TNSS) versus placebo for the fixed-dose combination of mometasone furoate and olopatadine hydrochloride. Mean TNSS was calculated over 6 hours at EEC for follow-up at Visit 5 (within 18 to 24 hours after first dose on Day 14) and is comparable to baseline TNSS at EEC at Visit 3 (over 6 hours before first dosing). ).

Change from study entry in mean TNSS after treatment for two fixed-dose mometasone furoate and olopatadine hydrochloride combination regimens with reference drugs: DYMISTA® Nasal Spray and PATANASE® Nasal Spray. Mean TNSS was calculated over 6 hours at EEC for follow-up at Visit 5 (within 18 to 24 hours after first dose on Day 14) and is comparable to baseline TNSS at EEC at Visit 3 (over 6 hours before first dosing). ).

Change from study entry in mean TNSS after treatment for two treatment regimens with a fixed dose combination of mometasone furoate and olopatadine hydrochloride, DYMISTA® nasal spray, and PATANASE® nasal spray. Mean post-treatment TNSS was calculated over 6 hours at EEC for follow-up at Visit 4 (within 1 to 7 hours after the first dose on Day 14) and is comparable to baseline TNSS at EEC at Visit 2 (over 6 hours) .

Change from study entry in mean TNSS after treatment for two fixed-dose mometasone furoate and olopatadine hydrochloride combination regimens compared to reference products: DYMISTA® Nasal Spray and PATANASE® Nasal Spray. Mean TNSS was calculated over 12 hours at the EEC for follow-up treatment (at Visit 4 for 1 to 7 hours after the first dose on Day 14, and at Visit 5 for 18 to 24 hours after the first dose on Day 14) and is comparable to baseline TNSS in EEC at visit 2 and visit 3 (over 12 hours prior to first dosing).

The onset of action for each fixed dose combination treatment of mometasone furoate and olopatadine hydrochloride, DYMISTA® and PATANASE® was assessed by comparing the change from baseline in post-treatment TNSS between each active treatment and placebo at each time point after the first treatment. Changes from entry into the study in TNSS were calculated at each time point after the first dose of study treatment in the EEC at Visit 3 (i.e., the last four hours in the EEC at Visit 3) with baseline (Visit 3) determined by as the average of the last two predosing time points.

Changes since entry into the study, mean after treatment, on the General Rhinitis Symptom Scale (TSS), Individual Rhinitis Symptom Scale (NSS, four nasal symptoms of rhinorrhea, itching, sneezing, and nasal congestion) and TOSS for 6 h in the EEC at Visit 5 and corresponding baseline at visit 3 (6 hours prior to first dosing).

Changes since entry into the study, mean after treatment, on the General Rhinitis Symptoms Scale (TSS), Individual Rhinitis Symptoms Scale (NSS, four nasal symptoms in the form of rhinorrhea,

- 28 041137 itching, sneezing and nasal congestion) and TOSS for 6 hours in the EEC at visit 4 and the corresponding baseline at visit 2 (over 6 hours in the EEC).

Changes since entry into the study, mean after treatment, on the General Rhinitis Symptom Scale (TSS), Individual Rhinitis Symptom Scale (NSS, four nasal symptoms of rhinorrhea, itching, sneezing, and nasal congestion) and TOSS for 12 hours in the EEC at Visit 4 and visit 5, and the corresponding baseline over 12 hours in EEC before dosing at visit 2 and visit 3.

Analysis of the EEC-QoLQ quality of life questionnaire for all treatment option groups by comparing 1) the preliminary EEC-QoLQ questionnaire at baseline (Visit 2) with the preliminary EEC-QoLQ questionnaire at Visit 4; 2) the post-EEC quality of life questionnaire at baseline, visit 2, with the post-EEC quality of life questionnaire at visit 4; 3) after 6 h in the EEC at visit 3 (before the first dosing) with a quality of life questionnaire after the EEC at visit 5.

Retrospective assessment of tolerability and acceptability for treatment option groups versus placebo after EEC at Visit 5.

results

In table. B provides an overview of the changes in TNSS from study entry to 6 h post-treatment in the EEC (ITT population).

Table B

Options placeb o TR-1 TR-2 DYMISTA® ® (comparisons) PATANASE (comparisons) N 36 36 36 36 36 Reference level with EEC Average 7.64 8.07 8.20 8.67 8.27 EEC at the end of treatment (2 weeks) Average 6.61 3.31 3.94 4.80 6.38 % Change from study entry 13.35 58.98 51.95 45.67 22.85

In table. C provides an overview of TNSS changes from study entry to 12 h post-treatment in the EEC (ITT population). (Data for NASONEX in Table C are from US FDA approved drug information).

___________________________________________________________ Table C

Options TR-1 TR-2 PATANASE® (comparisons) NASONEX®* DYMISTA® (comparisons) N 36 36 36 176 36 original level with EEC Average 7.58 7.85 7.90 9.60 8.25 EEC in end of treatment (2 weeks) Average 2.85 3.36 5.72 4.34 % Change since enrollment in the study 62.4 57.07 27.5 27.92 48.24

*NASONEX® (Mometasone Furoate Nasal Spray) US FDA Approved Drug Information (January 19, 2011)

In table. D provides an overview of TOSS changes from study entry to 12 h post-treatment in the EEC (ITT population).

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Table D

Options TR-1 TR-2 PATANASE® (comparisons) DYMISTA® (comparisons) N 36 36 36 36 Reference level with EEC Average 3.97 4.17 3.92 4.54 EEC at the end of treatment (2 weeks) Average 1.97 2.34 2.82 2.82 % Change from study entry 50.37 43.6 28.3 37.88

The results of the study show that the combination of mometasone furoate and olopatadine hydrochloride, when administered nasally to humans, provides effective treatment of seasonal allergic rhinitis and a clinically significant reduction in both nasal and non-nasal symptoms associated with it. The magnitude of this reduction for TNSS was clinically significant (i.e., greater than 2 units difference - which is generally considered clinically significant - between study drugs and placebo). Study drug-1 showed an overall better reduction in symptoms compared to the reference drugs (PATANASE® and DYMISTA®). Onset of action occurred within 10 min for TP-1 using iTNSS change from entry into the study after the first dose at Visit 3 (-1.26). However, onset of action could not be determined for TP-2, DYMISTA, and PATANASE because no statistically significant difference in iTNSS change from study entry between these treatments and placebo treatment was observed at any of the 2 consecutive time points.

Example 6 Phase II Clinical Study of Fixed Dose Mometasone and Olopatadine Nasal Spray Combination in Patients

The study is a double-blind, randomized, parallel-group comparison study to evaluate the efficacy, safety, and tolerability of two different dosages and treatment regimens for the fixed-dose combination of mometasone furoate and olopatadine hydrochloride nasal spray versus placebo nasal spray and individual monotherapy dosage forms in in the form of a nasal spray containing olopatadine hydrochloride and a nasal spray containing mometasone furoate in patients (12 years and older) with seasonal allergic rhinitis (SAR).

Basic goals

To compare the efficacy of mometasone furoate and olopatadine hydrochloride nasal spray once daily and mometasone furoate plus olopatadine hydrochloride nasal spray twice daily with placebo nasal spray and with individual compound monotherapies at the same dose in the same volume. same excipient for 14 days of study treatment.

To compare the onset of action between mometasone furoate and olopatadine hydrochloride nasal spray once daily and mometasone furoate with olopatadine hydrochloride nasal spray twice daily versus placebo versus individual compound monotherapies at the same dose at the same vehicle after the first dose of study drug.

Assess the safety and tolerability of selected groups by treatment options.

Table E Study drugs and their administration

Code Investigational drugs Introduction TR-1 Olopatadine hydrochloride + mometasone furoate (665 mcg + 25 mcg) nasal spray Twice a day (VS) in the morning and in the evening TR-2 Olopatadine hydrochloride + mometasone furoate (665 mcg + 50 mcg) nasal spray Once a day (QD) in the morning GO-1 Olopatadine hydrochloride (665 mcg) nasal spray Once a day (QD) in the morning

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GO-2 Olopatadine hydrochloride (665 mcg) nasal spray Twice a day (VS) in the morning and in the evening GM-1 Mometasone furoate (50 mcg) nasal spray Once a day (QD) in the morning GM-2 Mometasone furoate (25 mcg) nasal spray Twice a day (VS) in the morning and in the evening

Sample size:

The study included 1106 randomized patients (158 patients per treatment group).

Key criteria for patient selection:

Age >12 years, including both sexes.

Documented clinical history of seasonal allergic rhinitis (SAR) (at least 2 years prior to screening visit) with exacerbations (clinical manifestation of active symptoms), and demonstrating a documented positive skin prick test (SPT) (allergic papule diameter of at least 5 mm more than the control allergic papule), to the Mexican juniper allergen.

12-hour retrospective TNSS score >8 out of a possible 12, and Nasal Congestion Scale score >2 for morning (AM) assessment at Screening Visit (Visit 1).

Study design:

Patients were randomized to treatment in a ratio of 1:1:1:1:1:1:1 in the following seven groups according to treatment options at several study centers.

For this study, a double masked design was used, comprising two identical nasal spray bottles (one for morning (AM) dosing and one for evening (PM) dosing) (Table F). The α-double masking design provides adequate closure given that the compared regimens differ in dosing frequency (BID vs. QD).

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Table F. Treatment with two identical nasal spray bottles (2 sprays per nostril, total 4 sprays per bottle per day)

Code Group by treatment option Morning (AM) Evening (RM) 1st vial 2nd vial TR-1 Olopatadine hydrochloride (665 mcg) + mometasone furoate 25 mcg twice a day (V GO) Active substance Active substance TR-2 Olopatadine hydrochloride (665 mcg) + mometasone furoate 50 mcg once daily (QD) Active substance placebo GO-1 Olopatadine hydrochloride nasal spray (665 mcg) once daily (QD) Active substance placebo GO-2 Olopatadine hydrochloride nasal spray (665 mcg) twice daily (BID) Active substance Active substance GM-1 Mometasone furoate nasal spray (50 mcg) once daily (QD) Active substance placebo GM-2 Mometasone furoate nasal spray (25 mcg) twice daily (VS) Active substance Active substance Rio placebo nasal spray placebo placebo

This study consisted of four visits to the study center. After the first screening visit (Visit 1), patients who met all study eligibility criteria were required to complete a single-blind placebo run-in period of 7-10 days. After completion of the lead-in period, eligible patients meeting the randomization criteria were enrolled and randomized to one of seven treatment option groups. Patients received the drug according to the randomization list. Randomized patients were required to complete a 2-week (14-day) treatment period according to the protocol to evaluate the efficacy and safety of the prescribed treatment.

Main evaluation criteria (clinical endpoints):

Primary Endpoint

Change from entry into the study in mean patient-reported AM and RM scores of 12-hour rTNSS (TNSS retrospective score) over the 14-day treatment period.

Secondary Endpoints

Change from study entry to mean patient-reported AM and RM 12-hour iTNSS score (point-relevant TNSS score) during the 14-day treatment period.

Change from entry into the study in the mean score of patient-reported AM and PM 12-hour rTOSS (TOSS retrospective score) over the 14-day treatment period.

The onset of action for each treatment is assessed by comparing the change from baseline in post-treatment iTNSS between each treatment with the active substance and placebo at specific time points (before the first dose (pre-dose), 15, 30, 45, 60, 90, 120, 150 , 180, 210 and 240 min) after the first study treatment for 4 hours.

Change from study entry in the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) to day 15 between treatment option groups for patients with impaired quality of life at study entry, as determined by RQLQ score at randomization visit

- 32 041137 (RV) 3.0 or higher (RQLQ population).

Tertiary efficacy endpoints

Nasal symptoms:

Change from entry into the study in patient-reported rTNSS AM scores during the 14-day treatment period.

Change from study entry in patient-reported AM iTNSS score during the 14-day treatment period.

Change from study entry in patient-reported RM rTNSS score during the 14-day treatment period.

Change from study entry in patient-reported iTNSS RM score over the 14-day treatment period.

Changes since entry into the study in patient-reported retrospective assessment of individual nasal symptoms during the 14-day treatment period (AM, PM and mean AM and PM).

Changes since entry into the study in patient-reported time-relevant scores of individual nasal symptoms during the 14-day treatment period (AM, PM and mean AM and PM).

Change since entry into the study in the mean AM and PM of patient-reported rTNSS and iTNSS scores each day.

Change from entry into the study in patient-reported rTNSS and iTNSS AM scores for each day.

Change from entry into the study in patient-reported RM scores on the rTNSS and iTNSS scales for each day.

Eye symptoms:

Change from entry into the study in mean patient-reported AM and PM iTOSS score (relevant TOSS score so far) during the 14-day treatment period.

Change from study entry in patient-reported AM rTOSS score during the 14-day treatment period.

Change from study entry in patient-reported AM iTOSS score during the 14-day treatment period.

Change from entry into the study in patient-reported PM rTOSS scores during the 14-day treatment period.

Change from entry into the study in patient-reported iTOSS RM score over the 14-day treatment period.

Changes since entry into the study in patient-reported retrospective assessment of individual ocular symptoms during the 14-day treatment period (AM, PM and mean AM and PM).

Changes since entry into the study in patient-reported pertinent assessment of individual ocular symptoms during the 14-day treatment period (AM, PM and mean AM and PM).

Change since entry into the study in the mean AM and PM of patient-reported rTOSS and iTOSS for each day.

Change from entry into the study in patient-reported AM rTOSS and iTOSS scores for each day.

Change from entry into the study in each day's patient-reported PM rTOSS and iTOSS scores.

Non-nasal symptoms are assessed similarly to the ocular symptoms described above.

Physician Nasal Symptom Rating Scale (PNSS) and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ):

Physician Nasal Symptom Rating Scale (PNSS) and Physician Rating of Selected Nasal Symptoms on Day 15 (Visit 4).

Separate RQLQ ranges at Day 15 (Visit 4) for the RQLQ population (defined as patients with impaired quality of life at study entry).

RQLQ at Day 15 (Visit 4) for Full Sample Analysis (FAS).

results

In table. G shows an overview of the primary clinical endpoint (rTNSS) and secondary clinical endpoints (iTNSS, rTOSS, onset of action, and RQLQ) observed during phase II of this study. For comparison of combination therapy with monotherapy, a p-value below 0.05 is considered statistically significant.

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Table G

Primary Clinical Endpoint Secondary Clinical Endpoints Group by treatment option rTNSS iTNSS rTOSS Start of action RQLQ TR-2 compared with Pho -1.10* p<0.001* -1.10 p<0.001* -0.55 p=0.004* 150 min. Statistically significant at all time points after 150 minutes (except 180 minutes)* -0.48 p=0.004* TR-2 comparison cGO-1 -0.77 p=0.002* -0.86 p=0.0003* -0.36 p=0.65 n/a -0.29 p=0.085 TR-2 comparison with GM-1 -0.35 p=0.15 -0.34 p=0.145 -0.37 p=057 n/a -0.13 p=0.429 TP-1 compared to Pho -1.17* p<0.001* -1.10 p<0.001* -0.41 p=0.032 No statistical significance at all time points -0.56 p=0.0009* TP-1 comparison with GO-2 -0.49 p=0.048* -0.45 p=0.058 -0.03 p=0.849 N/A -0.25 p=0.135 TP-1 comparison with GM-2 -0.71 p=0.004* -0.65 p=0.006* -0.40 p=040* N/A -0.41 p=0.014*

* indicates statistical significance

As can be seen from Table. G, once-daily (TP-2) or twice-daily (TP-1) combination of mometasone furoate and olopatadine hydrochloride is statistically superior to placebo (p<0.0001) for primary endpoint, change in rTNSS from inclusion into research. The once-daily (TR-2) or twice-daily (TR-1) combination of mometasone furoate and olopatadine hydrochloride also met the study's secondary clinical endpoints, supporting its efficacy in the treatment of seasonal allergic rhinitis (SAR). The twice-daily combination of mometasone furoate and olopatadine hydrochloride (TP-1) was also statistically superior to individual monotherapies (GO-2 and GM-2) for both primary (rTNSS) and secondary endpoints (iTNSS).

Tab. G2 shows the difference in the RMS mean of the individual retrospective score on the General Rhinitis Symptoms Scale for TP-1 and TP-2 compared to placebo.

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Table G2

Difference in the RMS mean of the individual retrospective score on the General Rhinitis Symptoms Scale for TP-1 and TP-2 versus placebo TR-1 Difference rms mean (97.5% confidence interval) p-value Rhinorrhea -0.27 (-0.42, -0.12) <0.001 Nasal congestion -0.24 (-0.38, -0.99) <0.001 Itchy nose -0.27 (-0.43, -0.11) <0.001 Sneeze -0.39 (-0.57, -0.22) <0.001 TR-2 Rhinorrhea -0.26 (-0.40, -0.11) <0.001 Nasal congestion -0.22 (-0.37, -0.08) <0.001 Itchy nose -0.26 (-0.42, -0.10) <0.001 Sneeze -0.37 (-0.55, -0.20) <0.001

In table. H is a summary of the treatment-emergent adverse events (TEAE) observed during phase II of this study.

Table H

Pho (N=159) TR-2 (N=158) GM-1 (N=160) GO-1 (N=158) TP-1 (N=157) GM-2 (N=159) GO-2 (N=160) At least 1 TEAE 13 (8.2%) 15 (9.5%) 15 (9.4%) 17 (10.8%) 17 (10.8%) 10 (6.3%) 25 (15.6%) Dysgeusia 0 2 (1.3%) 0 2 (1.3%) 2 (1.3%) 0 5 (3.1%) cephalgia 1 (0.6%) 6 (3.8%) 2 (1.3%) 1 (0.6%) 0 1 (0.6%) 1 (0.6%)

All TEAEs were mild to moderate. Dysgeusia (1.3%) and cephalgia (1.9%) were adverse events (AEs) reported for the combination of twice-daily (BID) and once-daily (QD) mometasone furoate and olopatadine hydrochloride, respectively.

Example 7 Phase III Clinical Trial of a Fixed-Dose Mometasone and Olopatadine Nasal Spray Combination in Patients with SAR, Spring Season

This study is a double-blind, randomized, parallel-group comparison study to evaluate the efficacy, safety, and tolerability of a fixed-dose combination of mometasone furoate and olopatadine hydrochloride nasal spray versus placebo nasal spray and individual monotherapy nasal spray formulations containing olopatadine hydrochloride and mometasone furoate nasal spray in patients (12 years and older) with seasonal allergic rhinitis (SAR).

Objectives of the clinical trial

To compare the efficacy of mometasone furoate and olopatadine hydrochloride nasal spray twice daily versus placebo-nasal spray versus individual compound monotherapies at the same dose in the same vehicle over 14 days of study treatment.

Assess the safety and tolerability of selected groups by treatment options.

To investigate the pharmacokinetics (PK) of mometasone furoate and olopatadine hydrochloride nasal spray in a twice daily regimen.

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Table I. Investigational drugs and their administration

Code Investigational drugs Introduction TR-1 Olopatadine hydrochloride + mometasone furoate (665 mcg + 25 mcg) nasal spray Twice a day (VS) in the morning and in the evening GO-2 Olopatadine hydrochloride (665 mcg) nasal spray Twice a day (VS) in the morning and in the evening GM-2 Mometasone furoate (25 mcg) nasal spray Twice a day (VS) in the morning and in the evening

Sample size:

The study included 1180 randomized patients (295 patients per treatment group).

Key criteria for patient selection:

Age >12 years, including both sexes.

A documented clinical history of seasonal allergic rhinitis (SAR) (at least 2 years prior to the screening visit) with exacerbations (clinical manifestation of active symptoms) during the study season from seasonal Juniper Mexican pollen, and demonstrating a documented positive skin prick test (SPT) (allergic papule diameter at least 5 mm larger than control allergic papule), to Mexican juniper allergen.

12-hour retrospective TNSS score >8 out of a possible 12, and Nasal Congestion Scale score >2 for morning (AM) assessment at Screening Visit (Visit 1).

Study design:

Patients were randomized to treatment in a ratio of 1:1:1:1 in the following four groups according to treatment options at several study centers.

Table J. Treatment with two identical nasal spray bottles (2 sprays per nostril, total 4 sprays from each bottle per day)

Code Group by treatment option Morning (AM) Evening (RM) 1st vial 2nd vial TR-1 Olopatadine hydrochloride (665 mcg) + mometasone furoate 25 mcg twice daily (VS) Active substance Active substance GO-2 Olopatadine hydrochloride nasal spray (665 mcg) twice daily (VS) Active substance Active substance GM-2 Mometasone furoate nasal spray (25 mcg) twice daily (VS) Active substance Active substance Rio placebo nasal spray placebo placebo

This study consisted of four visits to the study center. After the first screening visit (Visit 1), patients who met all study eligibility criteria were required to complete a single-blind placebo run-in period of 7-10 days. After completion of the lead-in period, eligible patients meeting the randomization criteria were enrolled and randomized to one of four treatment option groups. Patients received the drug according to the randomization list. Randomized patients were required to complete a 2-week (14-day) treatment period according to the protocol to evaluate the efficacy and safety of the prescribed treatment. Patients were instructed to record symptom scores in a symptom score diary. They were also required to have at least two blood samples for PK assessment during the treatment period.

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Main evaluation criteria (clinical endpoints):

Primary Endpoint

Change from entry into the study in the mean score of patient-reported AM and

RM 12-hour rTNSS (TNSS retrospective assessment) during the 14 day treatment period.

Secondary Endpoints

Change from study entry to mean patient-reported AM and RM 12-hour iTNSS score (point-relevant TNSS score) during the 14-day treatment period.

Change from entry into the study in the mean score of patient-reported AM and PM 12-hour rTOSS (TOSS retrospective score) over the 14-day treatment period.

The onset of action for each treatment is assessed by comparing the change from baseline in post-treatment iTNSS between each treatment with the active substance and placebo at specific time points (before the first dose (pre-dose), 15, 30, 45, 60, 90, 120, 150 , 180, 210 and 240 min) after the first study treatment for 4 hours.

Change since entry into the study in overall score in the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) - Standardized Activity Score (RQLQ(S)) at Day 15 (Visit 4) for Full Sample Analysis (FAS).

Pharmacokinetic Endpoints

Plasma pharmacokinetics: Maximum plasma concentration (C _max ), time to reach C _max (T _max ) and area under the plasma concentration-time curve over the dosing interval (AUC _tau ) will be evaluated for mometasone furoate and olopatadine on day 1 and day 8 based on pharmacokinetic analysis set (PKAS).

Tertiary efficacy endpoints

Nasal symptoms:

Change from entry into the study in patient-reported rTNSS AM scores during the 14-day treatment period.

Change from study entry in patient-reported AM iTNSS score during the 14-day treatment period.

Change from study entry in patient-reported RM rTNSS score during the 14-day treatment period.

Change from study entry in patient-reported iTNSS RM score over the 14-day treatment period.

Changes since entry into the study in patient-reported retrospective assessment of individual nasal symptoms during the 14-day treatment period (AM, PM and mean AM and PM).

Changes from study entry in patient-reported, current assessment of individual nasal symptoms during the 14-day treatment period (AM, PM and mean AM and PM).

Change since entry into the study in the mean AM and PM of patient-reported rTNSS and iTNSS scores each day.

Change from entry into the study in patient-reported rTNSS and iTNSS AM scores for each day.

Change from entry into the study in patient-reported RM scores on the rTNSS and iTNSS scales for each day.

Eye symptoms:

Change from entry into the study in the mean score reported by AM and PM iTOSS patients (related to that point in TOSS score) during the 14-day treatment period.

Change from entry into the study in the score reported by AM rTOSS patients during the 14-day treatment period.

Change from entry into the study in the score reported by AM iTOSS patients during the 14-day treatment period.

Change from entry into the study in the score reported by RM rTOSS patients during the 14-day treatment period.

Change from entry into the study in the score reported by PM iTOSS patients during the 14-day treatment period.

Changes since entry into the study in patient-reported retrospective assessment of individual ocular symptoms during the 14-day treatment period (AM, PM and mean AM and PM).

Changes since entry into the study in patient-reported pertinent assessment of individual ocular symptoms during the 14-day treatment period (AM, PM and mean AM and PM).

Change since entry into the study in the mean AM and PM of patient-reported rTOSS and iTOSS for each day.

Change from entry into the study in the score reported by AM rTOSS and iTOSS patients for each day.

Change since entry into the study in the score reported by RM patients for rTOSS and iTOSS for each day.

Non-nasal symptoms are assessed similarly to the ocular symptoms described above.

Physician Nasal Symptom Rating Scale (PNSS), Rhinoconjunctivitis Quality of Life Questionnaire on Standardized Activities (RQLQ(S)), and Rhinitis Control Assessment Test (RCAT):

Change from study entry in Physician Nasal Symptom Rating Scale (PNSS) and Physician Assessment of Selected Nasal Symptoms at Day 15 (Visit 4).

Change from study entry in selected RQLQ(S) ranges to Day 15 (Visit 4) for FAS.

Change from study entry in total RQLQ(S) score and individual RQLQ(S) ranges on Day 15 (Visit 4) for the analyzed RQLQ(S) sample.

Change from enrollment in the RCAT to Day 15 (Visit 4).

Change from study entry in selected RCAT ranges to Day 15 (Visit 4).

Separate RQLQ ranges at Day 15 (Visit 4) for the RQLQ population (defined as patients with impaired quality of life at study entry).

RQLQ at Day 15 (Visit 4) for Full Sample Analysis (FAS).

results

In table. K shows an overview of the primary clinical endpoint (rTNSS) and secondary clinical endpoints (iTNSS, rTOSS, onset of action, and RQLQ) observed during Phase III of this study. For comparison of combination therapy with monotherapy, a p-value below 0.05 is considered statistically significant.

Table K

Primary Clinical Endpoint Secondary Clinical Endpoints Group by treatment option rTNSS iTNSS rTOSS Start of action RQLQ TP-1 compared to Pho -0.98 p<0.0001* -0.93 p<0.0001* -0.49 p=0.0014* 15 minutes. statistically significant at all time points -0.43 p=0.0001 TP-1 comparison with GO-2 -0.61 p=0.0029* -0.50 p=0.0050* -0.09 p=0.5423 n/a -0.28 p=0.0105 TP-1 comparison with GM-2 -0.39 p=0.058 -0.36 p=0.0413* -0.19 p=0.2113 n/a -0.20 p=0.0692 GO-2 by compared to Pho -0.37 p=0.075 -0.42 p=0.0177* -0.40 p=0.0100 statistically significant only at 45 minutes -0.15 p=0.1659 GM-2 by compared to Pho -0.59 p=0.004 -0.57 p=0.0017* -0.30 p=0.0510 No statistical significance at all time points -0.23 p=0.0345

* indicates statistical significance

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As can be seen from Table. K, the combination of mometasone furoate and olopatadine hydrochloride twice daily (TP-1) is statistically superior to placebo (p<0.0001) for the primary endpoint, change in rTNSS from study entry, and statistically superior to olopatadine hydrochloride monotherapy (GO -2). Secondary endpoints were also statistically significant for the twice-daily combination of mometasone furoate and olopatadine hydrochloride (TP-1), which supports its efficacy in the treatment of seasonal allergic rhinitis (SAR).

The twice-daily combination of mometasone furoate and olopatadine hydrochloride (TP-1) also showed a faster onset of action (onset of action within 15 minutes) as measured by iTNSS, compared with either olopatadine hydrochloride monotherapy or mometasone furoate monotherapy.

All TEAEs were mild to moderate. Dysgeusia (3.3%) and cephalgia (0.7%) were reported as adverse events for the twice-daily combination of mometasone furoate and olopatadine hydrochloride (BID).

The pharmacokinetics (PK) of TP-1 was measured in a subgroup of patients in a phase III clinical study on day 1 and day 8 (steady state). RK results for patients receiving TP1 are shown below.

PK parameter Olopatadin PK parameter mometasone furoate Day 1 Day 8 Day 1 Day 8 Stax (ng/ml) (n=26) (n=25) Stax (pg/ml) (n=26) (n=26) Mean value (SD) 19.82 (6.36) 19.80 (7.01) Mean value (SD) 6.78 (2.71) 9.92 (3.74) CV% 32.12 35.39 CV% 39.96 37.69 min-max 8.70- 31.60 EDUZU, 30 min-max 2.67- 12.80 3.58- 16.10 Geomean (Geo CV%) 18.77 (35.61) 18.Y0 (35.34) Geomean (Geo CV%) 6.27 (42.80) 9.17 (43.88) AUCtau (ng*h/ml) (n=26) (n=24) AUCtau (pg*h/ml) (n=26) (n=25) Mean value (SD) 75.48 (20.02) 88, WU (23.87) Mean value (SD) 28.56 (13.33) 58.40 (27.00) CV% 26.53 26.89 CV% 46.67 46.23 min-max 39.33- 116.80 53.35- 138.34 min-max 12.11- 72.54 25.68- 124.05 Geomean (Geo CV%) 72.90 (27.67) 85.74 (27.54) Geomean (Geo CV%) 26.16 (43.51) 52.67 (49.48) Tmax (h) (n=26) (n=26) Tmax (h) (n=26) (n=26) Median (range) 1.00 (0.25-3) 1.00 (0.25-2) Median (range) 1.00 (0.25-2) 1.00 (0.25-2)

Example 8 Phase III Clinical Trial of a Fixed-Dose Mometasone and Olopatadine Nasal Spray Combination in Patients with SAR, Autumn Season and Mexican Juniper

This study is a double-blind, randomized, parallel-group comparison study to evaluate the efficacy, safety, and tolerability of a fixed-dose combination of mometasone furoate and olopatadine hydrochloride nasal spray versus placebo nasal spray and individual monotherapy nasal spray formulations containing olopatadine hydrochloride and nasal spray containing mometasone furoate in patients (12 years of age and older) with seasonal allergic rhinitis (SAR), autumn season and Mexican juniper.

Objectives of the clinical trial

To compare the efficacy of mometasone furoate and olopatadine hydrochloride nasal spray twice daily versus placebo-nasal spray versus individual compound monotherapies at the same dose in the same vehicle over 14 days of study treatment.

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Assess the safety and tolerability of selected groups by treatment options.

Table L. Investigational drugs and their administration

Code Investigational drugs Introduction TR-1 Olopatadine hydrochloride + mometasone furoate (665 mcg + 25 mcg) nasal spray Twice daily (BID) morning and evening GO-2 Olopatadine hydrochloride (665 mcg) nasal spray Twice a day (VS) in the morning and in the evening GM-2 Mometasone furoate (25 mcg) nasal spray Twice a day (VS) in the morning and in the evening

Sample size:

The study included 1176 randomized patients (~294 patients per treatment group). For this study, the patient category is an adult and adolescent patient (12 years of age or older) with SAR who develop SAR symptoms during the fall allergy season to the relevant seasonal allergen (eg, ragweed).

Study design:

Patients were randomized to treatment in a ratio of 1:1:1:1 in the following four groups according to treatment options at several study centers.

Table M. Treatment with two identical nasal spray bottles (2 sprays per nostril, total 4 sprays per bottle per day)

Code Group by treatment option Morning (AM) Evening (RM) 1st vial 2nd vial TR-1 Olopatadine hydrochloride (665 mcg) + mometasone furoate 25 mcg twice daily (VS) Active substance Active substance GO-2 Olopatadine hydrochloride nasal spray (665 mcg) twice daily (VS) Active substance Active substance GM-2 Mometasone furoate nasal spray (25 mcg) twice daily (VS) Active substance Active substance Rio placebo nasal spray placebo placebo

This study consisted of four visits to the study center. After the first screening visit (Visit 1), patients who met all study eligibility criteria were required to complete a single-blind placebo run-in period of 7-10 days. After completion of the lead-in period, eligible patients meeting the randomization criteria were enrolled and randomized to one of four treatment option groups. Patients received the drug according to the randomization list. Randomized patients were required to complete a 2-week (14-day) treatment period according to the protocol to evaluate the efficacy and safety of the prescribed treatment. Patients were instructed to record symptom scores in a symptom score diary.

Main evaluation criteria (clinical endpoints):

Primary Endpoint

Change from entry into the study in mean patient-reported AM and RM scores of 12-hour rTNSS (TNSS retrospective score) during the 14-day treatment period.

Secondary Endpoints

Change from study entry to mean patient-reported AM and RM 12-hour iTNSS score (point-relevant TNSS score) during the 14-day treatment period.

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Change from entry into the study in the mean score of patient-reported AM and

PM 12-hour rTOSS (retrospective assessment of TOSS) during the 14-day treatment period.

The onset of action for each treatment is assessed by comparing the change from baseline in post-treatment iTNSS between each treatment with the active substance and placebo at specific time points (before the first dose (pre-dose), 15, 30, 45, 60, 90, 120, 150 , 180, 210 and 240 min) after the first study treatment for 4 hours.

Change since entry into the study in overall score in the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) - Standardized Activity Score (RQLQ(S)) at Day 15 (Visit 4) for Full Sample Analysis (FAS).

Tertiary efficacy endpoints

Nasal symptoms:

Change from entry into the study in patient-reported rTNSS AM scores during the 14-day treatment period.

Change from study entry in patient-reported AM iTNSS score during the 14-day treatment period.

Change from study entry in patient-reported RM rTNSS score during the 14-day treatment period.

Change from study entry in patient-reported iTNSS RM score over the 14-day treatment period.

Changes since entry into the study in patient-reported retrospective assessment of individual nasal symptoms during the 14-day treatment period (AM, PM and mean AM and PM).

Changes since entry into the study in patient-reported time-relevant scores of individual nasal symptoms during the 14-day treatment period (AM, PM and mean AM and PM).

Change since entry into the study in the mean AM and PM of patient-reported rTNSS and iTNSS scores each day.

Change from entry into the study in patient-reported rTNSS and iTNSS AM scores for each day.

Change from entry into the study in patient-reported RM scores on the rTNSS and iTNSS scales for each day.

Eye symptoms:

Change from entry into the study in mean patient-reported AM and PM iTOSS score (relevant TOSS score so far) during the 14-day treatment period.

Change from study entry in patient-reported AM rTOSS score during the 14-day treatment period.

Change from study entry in patient-reported AM iTOSS score during the 14-day treatment period.

Change from entry into the study in patient-reported PM rTOSS scores during the 14-day treatment period.

Change from entry into the study in patient-reported iTOSS RM score over the 14-day treatment period.

Changes since entry into the study in patient-reported retrospective assessment of individual ocular symptoms during the 14-day treatment period (AM, PM and mean AM and PM).

Changes since entry into the study in patient-reported pertinent assessment of individual ocular symptoms during the 14-day treatment period (AM, PM and mean AM and PM).

Change since entry into the study in the mean AM and PM of patient-reported rTOSS and iTOSS for each day.

Change from entry into the study in patient-reported AM rTOSS and iTOSS scores for each day.

Change from entry into the study in each day's patient-reported PM rTOSS and iTOSS scores.

Non-nasal symptoms are assessed similarly to the ocular symptoms described above.

Physician Nasal Symptom Rating Scale (PNSS), Rhinoconjunctivitis Quality of Life Questionnaire on Standardized Activities (RQLQ(S)), and Rhinitis Control Assessment Test (RCAT):

Change from study entry in Physician Nasal Symptom Rating Scale (PNSS) and Physician Assessment of Selected Nasal Symptoms at Day 15 (Visit 4).

Change from study entry in selected RQLQ(S) ranges to Day 15 (Visit 4) for FAS.

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Change from study entry in total RQLQ(S) score and individual RQLQ(S) ranges on Day 15 (Visit 4) for the analyzed RQLQ(S) sample.

Change since enrollment in the RCAT on Day 15 (Visit 4).

Change from study entry in selected RCAT ranges to Day 15 (Visit 4).

results

In table. N shows an overview of the primary clinical endpoint (rTNSS) and secondary clinical endpoints (iTNSS, rTOSS, onset of action, and RQLQ) observed during Phase III of this study. For comparison of combination therapy with monotherapy, a p-value below 0.05 is considered statistically significant.

TableN

Primary Clinical Endpoint Secondary Clinical Endpoints Group by treatment option rTNSS iTNSS rTOSS Start of action RQLQ TP-1 compared to Pho -1.09 (p<0.001)* -0.94 (p<0.001)* -0.52 (p=0.001)* 15 minutes. statistically significant at all time points. -0.45 (p=0.0001)* TP-1 compared to GO-2 -0.44 (p=0.028)* -0.41 (p=0.0035)* -0.17 (p=0.297)* n/a -0.31 (p=0.0090)* TP-1 comparison with GM-2 -0.47 (p=0.019)* -0.51 (p=0.008)* -0.35 (p=0.030)* n/a -0.09 (p=0.423)* GO-2 by compared to Pho -0.64 (p=0.001)* -0.54 (p=0.005)* -0.35 (p=0.029)* 15 minutes. statistically significant at all time points. -0.14 (p=0.221)* GM-2 by compared to Pho -0.62 (p=0.002)* -0.44 (p=0.023)* -0.17 (p=0.282)* No statistical significance at any time points. -0.36 (p=0.0024)*

* indicates statistical significance

As can be seen from Table. N, twice-daily combination of mometasone furoate and olopatadine hydrochloride (TP-1) is statistically superior to placebo (p<0.0001) for the primary endpoint, change in rTNSS from study entry, and statistically superior to olopatadine hydrochloride monotherapy ( GO-2) and mometasone furoate monotherapy (GM-2). Secondary endpoints were also statistically significant for the twice-daily combination of mometasone furoate and olopatadine hydrochloride (TP-1), which supports its efficacy in the treatment of seasonal allergic rhinitis (SAR).

Tab. N2 shows the difference in the RMS mean of the individual retrospective score and the so far score on the General Rhinitis Symptoms Scale for the TP-1 group compared to the placebo group.

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Table N2

Difference between the RMS mean of the individual retrospective score and the so far score on the Global Rhinitis Symptoms Scale for TP-1 versus placebo retrospective Difference rms mean (97.5% confidence interval) p-value Rhinorrhea -0.30(-0.41,-0.19) <0.001 Nasal congestion -0.20 (-0.30, -0.09) <0.001 Itchy nose -0.23 (-0.34, -0.12) <0.001 Sneeze -0.41 (-0.53, -0.29) <0.001 Pertaining to the moment Rhinorrhea -0.29 (-0.39, -0.18) <0.001 Nasal congestion -0.19 (-0.29, -0.09) <0.001 Itchy nose -0.21 (-0.32, -0.10) <0.001 Sneeze -0.29 (-0.41, -0.18) <0.001

The twice-daily combination of mometasone furoate and olopatadine hydrochloride (TP-1) also showed a faster onset of action (onset of action within 15 minutes) as measured by iTNSS, compared with either olopatadine hydrochloride monotherapy or mometasone furoate monotherapy.

All TEAEs were mild to moderate. Dysgeusia (3.8%), nasal discomfort (1%), and urinary tract infection (1%) were reported as adverse events for the twice-daily combination of mometasone furoate and olopatadine hydrochloride (BID).

Example 9 Phase III Clinical Trial of a Fixed-Dose Mometasone and Olopatadine Nasal Spray Combination in Patients

This study is a double-blind, randomized, parallel-group comparison study to evaluate the long-term safety, efficacy, and tolerability of a fixed-dose combination of mometasone furoate and olopatadine hydrochloride nasal spray versus two placebo nasal sprays in patients aged 12 years and older. ) with perennial allergic rhinitis (PAR).

Objectives of the clinical trial

To compare the long-term safety and tolerability of mometasone furoate and olopatadine hydrochloride nasal spray twice daily with two placebonasal sprays at the same dose in the same vehicle during 52 weeks of treatment in a study in patients with PAR .

A secondary objective is to evaluate the long-term efficacy of the fixed dose combination of mometasone furoate and olopatadine hydrochloride nasal spray versus placebonasal aerosol formulations (pH = 3.7) in patients with PAR.

Key criteria for patient selection:

Men and non-pregnant women aged >12 years.

A history of PAR for at least 2 years and a positive skin prick test for at least 1 relevant allergen.

Patient-reported retrospective Morning (AM) TNSS score >5 out of a possible 12, and Nasal Congestion Scale >2 for Morning (AM) score at screening visit (Visit 1).

At the end of the placebo run-in period to be eligible for randomization, the patient did not experience AE, which would result in non-compliance with screening inclusion criteria.

Patient-reported morning (AM) rTNSS score averaged 5 (out of a possible 12) during the last 4 days of the lead-in period (last 4 consecutive AM scores from day 3 of the AM score to the AM score on the day of randomization)

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Patient-reported retrospective morning (AM) score of nasal congestion averaging 2 or more during the last 4 days of the run-in period (last 4 consecutive AM scores from day 3 of the AM score to the AM score on the day of randomization)

Study design:

A total of 601 randomized patients were included in the study. Patients were randomized to treatment in a 4:1:1 ratio in 3 treatment groups across multiple centers. Treatment groups are presented in table. They are.

Table O. Investigational drugs and their administration

Code Investigational drugs Introduction TR-1 Olopatadine hydrochloride + mometasone furoate (665 mcg + 25 mcg) nasal spray Twice a day (VS) in the morning and in the evening Pho-1 Placebo nasal spray, pH 3.7 Placebo - twice a day (TS) in the morning and in the evening Pho-2 Placebo nasal spray, pH 7.0 Placebo - twice a day (TS) in the morning and in the evening

This study consisted of twelve visits to the study center. After the first screening visit (Visit 1), patients who met all study eligibility criteria underwent a single-blind placebo run-in period of 7-10 days. After completion of the lead-in period, eligible patients meeting the randomization criteria were enrolled and randomized to one of three treatment option groups. Randomized patients completed a 52-week treatment period according to the protocol to evaluate the efficacy and safety of the prescribed treatment.

Main evaluation criteria (clinical endpoints):

Primary Endpoints

Proportion of patients with adverse events occurring during treatment (TEAE).

Percentage of patients with treatment-related adverse events (TEAE).

Incidence, type and severity of TEAE after 30 weeks of study treatment.

Incidence, type and severity of TEAE after 52 weeks of study treatment.

Clinical laboratory evaluations (hematology, serum chemistry, and urinalysis) at study entry, week 30 and week 52.

Vital signs, physical examinations (PE) and ear, nose and throat (ENT) and eye examinations at study entry, week 30 and week 52.

Secondary Endpoints

Efficiency Endpoints

Change from entry into the study in mean patient-reported morning (AM) rTNSS scores during the first 6, 30, and 52 weeks of treatment.

Change from entry into the study in average patient-reported morning (AM) instantaneous global rhinitis symptom score (iTNSS) scores during the first 6, 30, and 52 weeks of treatment.

Change from entry into the study in overall score on the Rhinoconjunctivitis Quality of Life Questionnaire - Standardized Activity (RQLQ(S)) at weeks 6, 30, and 52 for Full Sample Analysis (FAS).

Additional performance endpoints

Additional endpoints included other patient-reported morning (AM) scores for individual nasal symptoms, patient-reported morning (AM) scores on the rTNSS and iTNSS scores from enrollment to the end of each week of treatment, Physician Nasal Symptom Rating Scale, and Physician Rating of Individual Nasal Symptoms. , individual RQLQ domains for the FAS population, and change from entry into the study in the Rhinitis Control Assessment Test and individual domains of the Rhinitis Control Assessment Test.

Data analysis

Full Sample Analysis (FAS) included all patients who were randomized to receive at least one dose of study drug and had at least one post-baseline efficacy assessment. This was a primary analysis designed to analyze effectiveness.

The per-protocol analysis population (PPS) consisted of a FAS subset that did not meet the PPS exclusion criteria. PPS was the secondary analysis sample for efficacy analysis (excluding RQLQ(S)).

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The safety analysis population (SAS) consisted of all patients who received at least one dose of study drug after randomization and were used for all safety analyses.

The analyzed RQLQ(S) sample consisted of all English-speaking patients >18 years of age with impaired quality of life at study entry, as determined by an RQLQ(S) score at the randomization visit (Visit 2) of 3.0 or greater.

Performance analysis

Efficiency analyzes were performed on FAS and PPS.

Change from study entry in mean AM rTNSS and iTNSS scores during the first 6, 30, and 52 weeks of treatment was analyzed using an analysis of covariance (ANCOVA) model for treatment group within the study, center, and baseline (defined as the mean of the last 4 consecutive AM assessments during the last 4 days of the run-in period from AM day 3 assessment to randomization day AM assessment). The difference in root mean square (LSMS) treatment and the associated 95% confidence intervals (95% CI) and p-values were presented.

Changes from entry into the study in rTNSS and iTNSS at the end of each week of treatment and change from baseline in individual nasal symptom scores during the first 6, 30, and 52 weeks (and at the end of each week of treatment) of the treatment period were analyzed as described above.

Changes from study entry in RQLQ(S) at weeks 6, 30, and 52 were analyzed for the analysis sample FAS and RQLQ(S) using ANCOVA models adjusted for study treatment group, center, and baseline RQLQ(S) (linear, continuous covariate). At each time point, only persons who had completed the corresponding visit were analyzed.

The analysis of the RCAT results was similar to the RQLQ(S) analysis, except that it was performed on FAS only.

Security Analysis

Adverse events occurring after the first dose of the randomized study drug were defined as TEAE.

The security endpoints associated with AE were

Percentage of patients with adverse events (TEAE).

Percentage of patients with treatment-related adverse events (TEAE).

Incidence, type and severity of TEAE after 30 weeks of study treatment.

Incidence, type and severity of TEAE after 52 weeks of study treatment.

results

Security Analysis

The table below shows the safety analysis for the three treatment groups over a 52 week period.

Security Analysis TR-1 Pbo-1 (pH=3.7) Pho-2 (pH = 7.0) Patients with at least one TEAE: η (%) 203 (52%) 41 (41%) 54 (54%) TEAE leading to termination: η (%) 15 (3.8%) 2 (2.0%) 3 (3.0%) SAE (all are not considered related) 7(1.5%) 2 (2.0%) 3 (1.5%)

As can be seen, there were no significant differences between the three treatment groups. Most TEAEs were mild to moderate in severity and were considered non-investigator related. TP-1 treatment was safe and well tolerated, and the safety profiles were consistent with those expected for the individual components of monotherapy. No deaths were reported during the study.

Performance analysis

The table below summarizes the results for the efficacy endpoint: Mean Nasal Symptom Score as AM Retrospective General Rhinitis Symptoms Scale (rTNSS, last 12 h) (Full Sample Analysis, FAS).

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TP-1 versus Pho-1 (pH = 3.7) 6 weeks 30 weeks 52 weeks N (TP-1 / Pbo-1) 319/99 391/99 391/99 Difference in treatment -0.81 -0.96 -0.91 95% CI -1.29, -0.32 -1.41, -0.50 -1.35, -0.47. p-value 0.0012* <0.0001* < 0.0001*

* Statistically significant

As can be seen, TP-1 showed a statistically significant and informative improvement in rTNSS compared to Pbo-1 (pH = 3.7) during the first 6, 30 and 52 weeks of the study.

The table below summarizes the results for the efficacy endpoint: Mean Nasal Symptom Score as AM of the So far General Rhinitis Symptom Scale (iTNSS, last 12 h) score (Full Sample Analysis, FAS).

TP-1 versus Pho-1 (pH = 3.7) 6 weeks 30 weeks 52 weeks N (TP-1 / Pho-1) 319/99 391/99 391/99 Difference in treatment -0.66 -0.83 -0.75 95% CI -1.12, -0.20 -1.26, -0.39 -1.17, -0.33 p-value 0.0053* 0.0002* 0.0005*

* Statistically significant

As can be seen, TP-1 showed a statistically significant and informative improvement in iTNSS compared to Pbo-1 (pH = 3.7) during the first 6, 30 and 52 weeks of the study.

The table below summarizes the results for the quality of life endpoint: RQLQ(S) (full sample analysis, FAS).

TP-1 versus Pho-1 (pH = 3.7) 6 weeks 30 weeks 52 weeks N (TP-1 / Pho-1) 371/95 322/84 286/72 Difference in treatment -0.42 -0.33 -0.04 95% CI -0.70,-0.14 -0.60, -0.05 -0.34, -0.26 p-value 0.0035* 0.0186* 0.7902

* Statistically significant

As can be seen, TP-1 showed a statistically significant and informative improvement in RQLQ (S) compared to Pbo-1 (pH = 3.7) during the first 6 and 30 weeks of the study.

Example 10 Pharmacokinetics of Olopatadine in Fixed Dose Combination Mometasone Furoate and Olopatadine Hydrochloride Nasal Spray

The pharmacokinetics of olopatadine in combination with a fixed dose of mometasone furoate and olopatadine hydrochloride nasal spray was evaluated in a clinical study. The clinical trial was a randomized, single-centre, single-dose, open-label, three-period, six-sequence, crossover study to evaluate three nasal spray treatments. The three treatments included a combination of mometasone furoate and olopatadine hydrochloride nasal spray, olopatadine hydrochloride nasal spray, and PATANASE® nasal spray.

Patients were randomized into 1 of 6 treatment sequences in a 1:1:1:1:1:1 ratio with all patients receiving single dose fixed dose combinations of mometasone furoate and olopatadine hydrochloride nasal spray, olopatadine hydrochloride nasal spray and nasal spray PATANASE®. The study consisted of a screening visit, 3 single-dose treatment periods with washout periods of 7 to 14 days between dosing in each treatment period, an early termination visit, if any, and a follow-up phone call (or visit) from 1 to 7 days after the end of the third treatment period.

A total of 30 patients were randomized to 1 of 6 treatment sequences and received at least 1 dose of study drug. All 30 patients were included in the safety analysis population and pharmacokinetic subgroup. All but 2 patients completed the study according to the protocol. The safety analysis population consisted of 30 patients: 29, 29 and 30 patients in the safety analysis population received a single dose fixed dose combination of mometasone furoate and olopatadine hydrochloride nasal spray, olopatadine hydrochloride nasal spray, and PATANASE® nasal spray, respectively. . The pharmacokinetic subgroup consisted of 30 patients: 29, 29 and 30 patients in the pharmacokinetic subgroup received a single dose fixed dose combination of mometasone furoate and olopatadine hydrochloride nasal spray, olopatadine hydrochloride nasal spray, and PATANASE® nasal spray, respectively.

Quantifiable concentrations of olopatadine were observed up to the last time point (48 hours). All 3 treatments were well tolerated. No patient died or reported a serious adverse event; and only one patient discontinued the study due to a treatment-induced adverse event (mild oropharyngeal pain) in this study. Treatment-induced adverse events and treatment-related adverse events were evenly distributed among the 3 treatment regimens. All treatment-induced adverse events were mild. There was no clinically significant effect of any of the treatments on laboratory parameters, vital signs, or ECG parameters.

Example 11 Pharmacokinetics of mometasone furoate in combination with a fixed dose of mometasone furoate and olopatadine hydrochloride nasal spray

The pharmacokinetics of mometasone furoate in combination with a fixed dose of mometasone furoate and olopatadine hydrochloride nasal spray was evaluated in a clinical study. The clinical trial was a randomized, single-centre, single-dose, open-label, three-period, six-sequence, crossover study to evaluate three nasal spray treatments. The three treatments included a combination of mometasone furoate and olopatadine hydrochloride nasal spray, mometasone furoate nasal spray, and Nasonex® nasal spray.

Patients were randomized to 1 of 6 treatment sequences in a 1:1:1:1:1:1 ratio with all patients receiving single dose fixed dose combinations of mometasone furoate and olopatadine hydrochloride nasal spray, mometasone furoate nasal spray, and nasal spray Nasonex ®. The study consisted of a screening visit, 3 single-dose treatment periods with washout periods of 7 to 14 days between dosing in each treatment period, an early termination visit, if any, and a follow-up phone call (or visit) from 1 to 7 days after the end of the third treatment period.

A total of 30 patients were randomized to 1 of 6 treatment sequences and received at least 1 dose of study drug. All 30 patients were included in the safety analysis population and pharmacokinetic subgroup. All but 2 patients completed the study according to the protocol. The safety analysis population consisted of 30 patients: 29, 29 and 30 patients in the safety analysis population received a single dose fixed dose combination of mometasone furoate and olopatadine hydrochloride nasal spray, mometasone furoate nasal spray, and Nasonex® nasal spray. respectively. The pharmacokinetic subgroup consisted of 30 patients: 29, 29 and 30 patients in the pharmacokinetic subgroup received a single dose fixed dose combination of mometasone furoate and olopatadine hydrochloride nasal spray, mometasone furoate nasal spray and Nasonex® nasal spray, respectively.

Quantifiable mometasone furoate concentrations were observed up to the last time point (72 hours). All 3 treatments were well tolerated. No patient died or reported a serious adverse event; or discontinued the study due to a treatment-induced adverse event in that study. Treatment-induced adverse events were evenly distributed among the 3 treatment regimens. All treatment-induced adverse events were mild. There was no clinically significant effect of any of the treatments on laboratory parameters, vital signs, or ECG parameters.

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Therapy Pharmacokinetic parameters AUC(o-t) AU C (0 -infinity) Stakh Ttah Olopatadine in combination with a fixed dose of mometasone furoate and olopatadine hydrochloride nasal spray 70.95 ng*h/ml 83.26 ng*h/ml 17.27 ng/ml 1.00 h Mometasone furoate in combination with a fixed dose of mometasone furoate and olopatadine hydrochloride nasal spray 84.97 pg*h/ml 103.77 pg*h/ml 10.81 pg/ml 1.00 h Relative bioavailability of the fixed dose combination of mometasone furoate and olopatadine hydrochloride nasal spray: Patanase® (Geometric Average Ratio %) 87.87 93.80 84.68 Nasonex® (Geometric Average Ratio %) 109.92 115.14 141.84 Olopatadin Hydrochloride (Geometric Average Ratio %) 86.92 92.83 86.63 Mometasone Furoate (Geometric Average Ratio%) 118.36 118.50 113.83

Example 12 Phase III Clinical Trial of a Fixed-Dose Mometasone and Olopatadine Nasal Spray Combination in Pediatric Patients

This study is a double-blind, randomized, parallel-group, 12-week study to evaluate the efficacy, safety, and tolerability of a fixed-dose combination of mometasone furoate and olopatadine hydrochloride nasal spray versus placebo nasal spray in pediatric patients (from 2 years to 12 years) with perennial seasonal allergic rhinitis (PAR).

Objectives of the clinical trial

To compare the efficacy of mometasone furoate and olopatadine hydrochloride nasal spray (administered as 1 spray per nostril twice daily) with placebo-nasal spray for the treatment of pediatric patients (aged 2 to 12 years) with PAR.

The secondary objective is to compare the safety and tolerability of a nasal spray containing mometasone furoate and olopatadine hydrochloride with a placebo nasal spray during 12 weeks of study treatment.

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Key Patient Selection Criteria

Male and non-pregnant female patients aged 2 to 12 years, on the date of the screening visit (Visit 1).

Documented clinical history of PAR (>12 months for patients aged >6 to <12 years, >6 months for patients aged >2 to <6 years preceding the screening visit (Visit 1)) with exacerbations (clinical manifestation of active symptoms). In the investigator's opinion, PAR must have been severe enough to have required treatment (both continuous and intermittent) in the past and is expected to require treatment throughout the study.

Documented positive skin prick test (allergic papule diameter 3 mm larger than negative allergic papule) for at least one allergen known to cause PAR. Documentation of a positive result within 12 months prior to the screening visit (Visit 1) is acceptable. A positive allergen test for the patient, which must match the PAR medical history. In addition, the patient is expected to be exposed to the PAR allergen for which he or she tests positive in a skin prick test for the duration of the study.

12-hour rTNSS score >6 (out of a possible 12) for the morning (AM) score at the screening visit (Visit 1).

Study Design

The study will randomize approximately 540 patients (2 to 12 years of age) in a 2:1 ratio to a fixed dose combination of mometasone furoate and olopatadine hydrochloride nasal spray (360 patients) versus placebo nasal spray (180 patients).

The duration of the study is 12 weeks. Patient participation can last from 13 to 14 weeks, consisting of a 7 to 10 day screening/placebo run-in period and a 12 week treatment period with an allowable variance from the schedule for study visits. Treatment groups are presented in the table below.

Investigational drugs and their administration

Investigational drugs Introduction Olopatadine hydrochloride + mometasone furoate (665 mcg + 25 mcg) nasal spray 1 spray per nostril, twice a day (VS) morning and evening placebo nasal spray Placebo - 1 spray per nostril twice a day (VS) in the morning and in the evening

* - Each spray provides 665 micrograms of olopatadine hydrochloride and 25 micrograms of mometasone furoate.

Primary Endpoint:

Change from entry into the study in the mean of the morning (AM) and evening (PM) patient-reported 12-hour retrospective global rhinitis symptom score (rTNSS) score during the first 4 weeks of treatment for patients >6 to <12 years of age.

Secondary Endpoint(s):

Change from entry into the study in the mean of the morning (AM) and evening (PM) patient-reported 12-hour Relevant General Rhinitis Symptoms Scale (iTNSS) score during the first 4 weeks of treatment for patients aged >6 to < 12 years old.

Change from entry into the study in the mean of patient-reported morning (AM) and evening (PM) 12-hour rTNSS scores during the first 4 weeks of treatment for patients >2 to <12 years of age.

Change from entry into the study in the mean of patient-reported morning (AM) and evening (PM) 12-hour iTNSS score during the first 4 weeks of treatment for patients >2 to <12 years of age.

Change from entry into the study in the overall pediatric rhinoconjunctivitis quality of life questionnaire (PRQLQ) score at week 4 among treatment groups.

Additional endpoint(s)

Nasal symptoms:

TNSS - first 4 weeks, patients aged >6 to <12 years:

Change from study entry in patient-reported morning (AM) rTNSS score during the first 4 weeks of treatment.

Change from entry into the study in patient-reported evening scores (PM) on the rTNSS during the first 4 weeks of treatment.

Change from study entry in patient-reported morning (AM) score to

- 49 041137 iTNSS scale during the first 4 weeks of treatment.

Change from entry into the study in patient-reported evening scores (PM) on the iTNSS scale during the first 4 weeks of treatment.

Changes since entry into the study in patient-reported retrospective assessment of individual nasal symptoms during the first 4 weeks of the treatment period (AM, PM and mean AM and PM).

Changes since entry into the study in patient-reported current scores of individual nasal symptoms during the first 4 weeks of the treatment period (AM, PM and mean AM and PM).

Changes since study entry in patient-reported rTNSS and iTNSS scores for each day (AM, PM and mean AM and PM).

TNSS - first 4 weeks, patients aged >2 to <6 years:

Change from study entry to the mean morning (AM) and evening (PM) patient-reported 12-hour rTNSS score during the first 4 weeks of treatment for patients >2 to <6 years of age.

Change from entry into the study in the mean of patient-reported morning (AM) and evening (PM) 12-hour iTNSS score during the first 4 weeks of treatment for patients >2 to <6 years of age.

TNSS - first 4 weeks, patients aged > 2 to < 12 years:

Change from entry into the study in the mean of patient-reported morning (AM) and evening (PM) 12-hour rTNSS scores during the first 4 weeks of treatment for patients >2 to <12 years of age.

Change from entry into the study in the mean of patient-reported morning (AM) and evening (PM) 12-hour iTNSS score during the first 4 weeks of treatment for patients >2 to <12 years of age.

Additional total rhinitis symptom scale (TNSS) scores will be scored for the following (e.g., AM, RM, individual symptoms):

weeks, patients aged >6 to <12 years.

weeks, patients aged >2 to <6 years.

weeks, patients aged >2 to <12 years.

Physician Nasal Symptom Rating Scale (PNSS):

Change from study entry in Physician Nasal Symptom Rating Scale (PNSS) and Physician Assessment of Individual Nasal Symptoms at Weeks 4 and 12.

Pediatric quality of life questionnaire for patients with rhinoconjunctivitis (PRQLQ):

Separate PRQLQ ranges at 4 and 12 weeks.

Example 13 Phase III Clinical Trial of a Fixed-Dose Mometasone and Olopatadine Nasal Spray Combination in Pediatric Patients

This study is a double-blind, randomized, parallel-group, 14-day study to evaluate the efficacy, safety, and tolerability of a fixed-dose combination of mometasone furoate and olopatadine hydrochloride nasal spray versus placebo nasal spray for 14 days in patients children (6 years to 12 years of age) with seasonal allergic rhinitis (SAR).

Objectives of the clinical trial

To compare the efficacy of mometasone furoate and olopatadine hydrochloride nasal spray (administered as 1 spray per nostril twice daily) with placebo-nasal spray for the treatment of pediatric patients (>6 to <12 years of age) with SAR.

The secondary objective is to compare the safety and tolerability of the nasal spray containing mometasone furoate and olopatadine hydrochloride with placebo nasal spray during the study period.

Key Patient Selection Criteria

Male and non-pregnant female patients aged >6 to <12 years at the date of the screening visit (Visit 1).

Documented clinical history of SAR (within at least 2 years preceding the screening visit (Visit 1)) with exacerbations (clinical manifestation of active symptoms) during the study season for the relevant seasonal allergen (tree/grass pollen). The SAR must have been severe enough to have required treatment (both continuous and intermittent) in the past and, in the opinion of the investigator, is expected to require treatment throughout the study period.

Shown to be susceptible to at least 1 seasonal allergen (tree/grass pollen) known to induce SAR by a documented skin prick test (allergic papule diameter at least 5 mm larger than negative control) to the corresponding seasonal allergen. Documentation of a positive result within 12 months prior to the screening visit (Visit 1) is acceptable. The patient's positive allergen must match the SAR medical history. In addition, the patient is expected to be adequately exposed to the SAR allergen for which he or she tests positive for the duration of the study.

Value of 12-hour retrospective General Rhinitis Symptom Scale (rTNSS) score >6 (out of a possible 12) for the morning (AM) score at the screening visit (Visit 1).

Study Design

Approximately 450 patients (>6 to <12 years) will be randomized in a 1:1 ratio to a fixed dose combination of mometasone furoate and olopatadine hydrochloride nasal spray (225 patients) versus placebo nasal spray (225 patients). .

Treatment groups are presented in the table below.

Investigational drugs and their administration

Investigational drugs Introduction Olopatadine hydrochloride + mometasone furoate (665 mcg + 25 mcg) nasal spray 1 spray per nostril, twice a day (VS) morning and evening placebo nasal spray Placebo - 1 spray per nostril twice a day (VS) in the morning and in the evening

*Each spray provides 665 mcg of olopatadine hydrochloride and 25 mcg of mometasone furoate.

Patient participation can last from 22 to 27 days, with a 7 to 10 day screening/placebo run-in period and a 14 day treatment period with a tolerance for study visits.

Key Evaluation Criteria (Clinical Endpoints)

Primary Endpoint:

Change from study entry to the mean of the morning (AM) and evening (PM) patient-reported 12-hour retrospective General Rhinitis Symptoms Scale (rTNSS) score over the 14-day treatment period.

Secondary Endpoint(s):

Change from entry into the study in mean patient-reported AM and RM 12-hour Relevant Global Rhinitis Symptoms Scale (iTNSS) score so far during the 14-day treatment period.

Change from entry into the study in the overall pediatric rhinoconjunctivitis quality of life questionnaire (PRQLQ) score on Day 15 (Visit 4) among treatment groups.

Change from study entry to the mean of the morning (AM) and evening (PM) patient-reported 12-hour retrospective total eye symptom score (rTOSS) score over the 14 day treatment period.

Additional Efficiency Endpoint(s):

nasal symptoms

Change from entry into the study in patient-reported rTNSS AM scores during the 14-day treatment period.

Change from entry into the study in the score reported by AM iTNSS patients during the 14-day treatment period.

Change from entry into the study in the score reported by RM rTNSS patients during the 14-day treatment period.

Change from entry into the study in the score reported by iTNSS RM patients during the 14-day treatment period.

Changes since entry into the study in patient-reported retrospective assessment of individual nasal symptoms during the 14-day treatment period (AM, PM and mean AM and PM).

Changes since entry into the study in patient-reported time-relevant scores of individual nasal symptoms during the 14-day treatment period (AM, PM and mean AM and PM).

Change since entry into the study in the mean AM and PM of patient-reported rTNSS and iTNSS scores each day.

Change from entry into the study in patient-reported rTNSS and iTNSS AM scores for each day.

Change since inclusion in the study in patient-reported RM scores on scales

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Claims (1)

rTNSS and iTNSS for each day. Eye symptoms Change from study entry to the mean of patient-reported morning (AM) and evening (PM) current total eye symptom score (iTOSS) scores over the 14 day treatment period. Change from entry into the study in the score reported by AM rTOSS patients during the 14-day treatment period. Change from entry into the study in the score reported by AM iTOSS patients during the 14-day treatment period. Change from entry into the study in the score reported by RM rTOSS patients during the 14-day treatment period. Change from entry into the study in the score reported by PM iTOSS patients during the 14-day treatment period. Changes since entry into the study in patient-reported retrospective assessment of individual ocular symptoms during the 14-day treatment period (AM, PM and mean AM and PM). Changes from study entry in patient-reported, current assessment of individual ocular symptoms during the 14-day treatment period (AM, PM and mean AM and PM). Change since entry into the study in the mean AM and PM of patient-reported rTOSS and iTOSS for each day. Change from entry into the study in the score reported by AM rTOSS and iTOSS patients for each day. Change since entry into the study in the score reported by RM patients for rTOSS and iTOSS for each day. Non-nasal symptoms will be scored similarly to the ocular symptoms described above (as described in the Statistical Analysis Plan (SAP)). Physician Nasal Symptom Rating Scale (PNSS): Change from study entry in Physician Nasal Symptom Rating Scale (PNSS) and Physician Assessment of Selected Nasal Symptoms at Day 15 (Visit 4). Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) Change from study entry in selected PRQLQ ranges to day 15. While the present invention has been described with reference to specific embodiments of the invention, it should be understood that these embodiments are merely illustrative of the principles and practice of the present invention. Therefore, it should be understood that numerous modifications may be made to the exemplary embodiments of the invention and that other devices may be devised without departing from the spirit and scope of the present invention as described. All publications, patents and patent applications mentioned in this application are incorporated herein by reference to the same extent as if each individual publication, patent or patent application were specifically and separately indicated for inclusion by reference. CLAIM 1. A dispensing device containing a pharmaceutical composition for nasal administration to a person, containing a container having an inner part of the bottom of a conical shape, while the inner part of the bottom has a downward slope from the side wall of the container in the direction of the center, and the center is located along the longitudinal axis of the container, in addition, the inner the bottom part contains an additional recessed at an angle hole, located in the center around the longitudinal axis, while the center is the lowest point of the inner part of the bottom of the container; a dispenser head for dispensing a pharmaceutical composition from a container, the dispenser head comprising at least a pump, a supply channel, and a spray orifice; a dip tube extending along the longitudinal axis of the container, the dip tube having a proximal end communicating with the dispenser head and an open distal end extending into the well, and an aqueous pharmaceutical composition in the container, the composition containing from about 0.001 to about 0.075% by weight mometasone, its ester or its salt in the form of particles; from about 0.5 to about 0.8% by weight of olopatadine or a salt thereof in dissolved form and a hydrocolloid in an amount sufficient to inhibit phase separation for at least -