Fluticasone furoate micelle-form solution and preparation method and application thereof

Abstract

The invention provides a fluticasone furoate micellar solution. The fluticasone furoate micellar solution comprises fluticasone furoate, a lipophilic component and a nonionic surfactant. According to the fluticasone furoate pharmaceutical composition, the dissolution rate and the absorption rate of fluticasone furoate on nasal mucosa and alveolar mucosa can be remarkably improved, and the administration dosage can be further reduced while the same curative effect is obtained, so that the toxic and side effects are reduced. The aerosol inhalation powder is especially suitable for aerosol inhalation, can provide better pulmonary deposition, and is especially suitable for nasal administration to reduce the administration dosage and improve the bioavailability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a fluticasone furoate micelle solution, its preparation method, and its uses. Background Technology

[0002] Fluticasone furoate is used to treat asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, sinusitis, and nasal polyps. Traditional fluticasone furoate inhalation dry powder has shown some shortcomings in terms of pulmonary disposition and efficacy in treating asthma and COPD. Furthermore, administration via dry powder inhalation is more difficult, especially for children and elderly patients. Simultaneously, dry powder inhalation may cause pulmonary side effects. The original formulation of traditional fluticasone furoate nasal spray contains suspending agents, and since fluticasone furoate is an insoluble suspension of particles, while the nasal spray is a suspension with a certain viscosity, this significantly affects its dissolution and absorption rates, resulting in high dosage and slow onset of action. Therefore, it is necessary to develop a new formulation of fluticasone furoate to overcome the shortcomings of existing inhalation and nasal spray formulations. Summary of the Invention

[0003] In order to overcome the shortcomings of the prior art, the purpose of this invention is to provide a fluticasone furoate micelle solution, its preparation method and uses.

[0004] The objective of this invention is achieved through the following technical solution:

[0005] A fluticasone furoate micelle solution, the solution comprising the following components:

[0006] 0.005%-1.5wt% fluticasone furoate, 0.5%-20.0wt% lipophilic components and nonionic surfactants, with the balance being water.

[0007] According to an embodiment of the present invention, the fluticasone furoate micelle solution is a nanomicelle.

[0008] According to some embodiments of the present invention, the micelle size D10 of the fluticasone furoate solution is 5nm-100nm, preferably 10nm-80nm, for example 15nm, 30nm, 45nm, 50nm, 60nm, 65nm, or 70nm.

[0009] According to an embodiment of the present invention, the micelle size D50 of the fluticasone furoate solution is 100nm-1200nm, preferably 120nm-1100nm, for example 150nm, 200nm, 300nm, 400nm, 500nm, 600nm, 700nm, 800nm, 900nm, or 1000nm.

[0010] According to an embodiment of the present invention, the micelle size D90 of the fluticasone furoate solution is 400nm-3500nm, preferably 500nm-3400nm, for example 600nm, 1000nm, 1400nm, 1800nm, 2000nm, 2300nm, 2500nm, 2800nm, 3000nm, 3200nm, and 3300nm.

[0011] According to an embodiment of the present invention, the fluticasone furoate micelle solution does not contain a suspending agent, such as microcrystalline cellulose-sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, etc.

[0012] According to an embodiment of the present invention, the water is water for injection.

[0013] According to some embodiments of the present invention, the mass percentage of fluticasone furoate is 0.005%-1.5 wt%, preferably 0.015%-1.0 wt%, for example 0.015 wt%, 0.03 wt%, 0.05 wt%, 0.08 wt%, 0.1 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, and 0.9 wt%.

[0014] According to some embodiments of the present invention, the sum of the mass percentages of the lipophilic component and the nonionic surfactant is 0.5%-20.0 wt%, preferably 1.5%-11.5 wt%, for example 1.5 wt%, 2.0 wt%, 2.5 wt%, 2.7 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 5.0 wt%, 6.0 wt%, 8.0 wt%, 10.0 wt%, 11.0 wt%, and 11.5 wt%.

[0015] According to some embodiments of the present invention, the lipophilic component and the nonionic surfactant are selected from one or more of Span (e.g., Span 85), HSPC (hydrogenated soybean phosphatidylcholine), DPPC (dispalmitoyl phosphatidylcholine), DOPC (dioleoyl lecithin), egg yolk lecithin, soybean lecithin, cholesterol, short-chain / medium-chain / long-chain fatty acid triesters, vitamin E succinate polyethylene glycol ester, oleic acid, polysorbate (Tween), caprylic / capric acid glycerol, HS-15 (15-hydroxystearic acid polyethylene glycol), and isopropyl myristate; preferably, they are selected from one or more of Span (e.g., Span 85), DPPC, HSPC, vitamin E succinate polyethylene glycol ester, short-chain / medium-chain / long-chain fatty acid triesters, HS-15, caprylic / capric acid glycerol, egg yolk lecithin, soybean lecithin, and polysorbate (e.g., polysorbate 80).

[0016] According to some embodiments of the present invention, the lipophilic component is selected from one or more of Span (e.g., Span 85), DPPC, HSPC, DOPC, soybean lecithin, egg yolk lecithin, cholesterol, DSPE-PEG1000, and short-chain / medium-chain / long-chain fatty acid triesters.

[0017] According to some embodiments of the present invention, the nonionic surfactant is selected from one or more of the following: polyethylene glycol succinate, HS-15, polyethylene glycol glycerol octanoate, polysorbate (e.g., polysorbate 80), and isopropyl myristate.

[0018] According to some embodiments of the present invention, the lipophilic component is 0.05%-1.5wt% by mass, preferably 0.1%-1.5wt%, for example 0.1wt%, 0.2wt%, 0.3wt%, 0.4wt%, 0.5wt%, 1.0wt%, and 1.5wt%.

[0019] According to embodiments of the present invention, the nonionic surfactant is present in a mass percentage of 1.0%-19.95 wt%, preferably 2.0%-10.0 wt%, for example 2.0 wt%, 2.2 wt%, 2.4 wt%, 2.6 wt%, 2.8 wt%, 3.0 wt%, 4.0 wt%, 5.0 wt%, 5.7 wt%, 6.0 wt%, 8.0 wt%, and 10.0 wt%.

[0020] According to some embodiments of the present invention, the mass ratio of the lipophilic component to the nonionic surfactant is 1:1-30, preferably 1:2-20, for example 1:4, 1:5, 1:6, 1:7, 1:8, 1:10, 1:12, 1:15, 1:16, 1:18, 1:19, 1:20.

[0021] According to an embodiment of the present invention, the lipophilic component and the nonionic surfactant are selected from the following combinations:

[0022] Combinations of short-chain / medium-chain / long-chain fatty acid triesters with polyethylene glycol succinate and vitamin E succinate, combinations of egg yolk lecithin with polysorbate 80, combinations of soybean lecithin with polysorbate 80, combinations of Span 85 with polysorbate 80, combinations of DPPC with polysorbate 80, combinations of HSPC with HS-15, combinations of egg yolk lecithin with polyethylene glycol succinate and soybean lecithin with polyethylene glycol succinate.

[0023] According to an embodiment of the present invention, the fluticasone furoate micelle solution further comprises a pH adjuster.

[0024] According to an embodiment of the present invention, the pH adjuster is selected from any one or more of disodium hydrogen phosphate, citric acid, hydrochloric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, boric acid and its salts, sodium citrate, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; preferably, the pH adjuster is selected from any one or more of hydrochloric acid, disodium hydrogen phosphate, and citric acid.

[0025] According to an embodiment of the present invention, the pH adjuster has a mass percentage of 0.05%-1.0 wt%, preferably 0.1%-0.5 wt%, for example 0.1 wt%, 0.2 wt%, 0.3 wt%, or 0.4 wt%.

[0026] According to an embodiment of the present invention, the pH value of the fluticasone furoate micelle solution is 3.0-7.0, more preferably 3.5-7.0, for example 3.5, 4.0, 4.55, 4.58, 4.6, 4.61, 4.65, 4.7, 5.0, 6.0, 6.41, 6.47, 7.0.

[0027] According to an embodiment of the present invention, the fluticasone furoate micelle solution further comprises an osmotic pressure regulator.

[0028] According to an embodiment of the present invention, the osmotic pressure regulator is selected from one or more of sodium chloride, potassium chloride, magnesium chloride, glucose, glycerol, propylene glycol, sorbitol, and mannitol; preferably, it is selected from one or more of sodium chloride, potassium chloride, magnesium chloride, and glucose.

[0029] According to an embodiment of the present invention, the osmotic pressure regulator has a mass percentage of 0.1%-2.0 wt%, preferably 0.2%-1.0 wt%, for example 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, or 1.5 wt%.

[0030] According to an embodiment of the present invention, the fluticasone furoate micelle solution further comprises a chelating agent.

[0031] According to an embodiment of the present invention, the chelating agent is selected from disodium edetate.

[0032] According to an embodiment of the present invention, the chelating agent is present in a mass percentage of 0.01%-0.1wt%, preferably 0.01%-0.05wt%, for example 0.01wt%, 0.02wt%, 0.03wt%, 0.04wt%, or 0.05wt%.

[0033] According to an embodiment of the present invention, the fluticasone furoate micelle solution further comprises an antibacterial agent.

[0034] According to an embodiment of the present invention, the antibacterial agent is selected from benzalkonium chloride, potassium sorbate, benzyl alcohol, and phenylethanol.

[0035] According to an embodiment of the present invention, the antibacterial agent is present in a mass percentage of 0.01%-0.5 wt%, preferably 0.01%-0.2 wt%, for example 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0.1 wt%, or 0.2 wt%.

[0036] According to an embodiment of the present invention, the fluticasone furoate micelle solution further comprises a solubilizer.

[0037] According to an embodiment of the present invention, the solubilizer is selected from one or more of propylene glycol, glycerol, cyclodextrin, and PEG 600.

[0038] According to an embodiment of the present invention, the mass percentage of the solubilizer is 0.1%-2.0 wt%, preferably 0.5-1.8 wt%, for example 0.6 wt%, 0.85 wt%, 1.0 wt%, 1.5 wt%.

[0039] According to an embodiment of the present invention, the fluticasone furoate micelle solution is a colorless solution with an opalescent appearance.

[0040] According to embodiments of the present invention, the encapsulation efficiency of the fluticasone furoate micelles is above 90%, for example 90.5%, 91.7%, 92.1%, 92.2%, 92.8%, 92.9%, 93%, 93.8%, 94.4%; the drug loading is 1.65%-2%, for example 1.68%, 1.69%, 1.7%, 1.71%, 1.72%, 1.73%, 1.76%, 1.78%, 1.86%. %; viscosity (mPa.S) is 7.2-10, e.g. 7.2, 7.5, 7.7, 7.8, 7.9, 8.0, 8.1, 8.8, 8.9, 9.8; aerodynamic particle size distribution (FPF) is 41-47%, e.g. 41.9%, 43.6%, 43.8%, 43.9%, 44%, 44.4%, 44.7%, 45%, 45.5%, 45.9%, 46.2%, 46.6%.

[0041] According to an embodiment of the present invention, the osmotic pressure of the fluticasone furoate micelle solution is 270 mOsm-520 mOsm, preferably 280 mOsm-470 mOsm, for example 285 mOsm, 290 mOsm, 295 mOsm, 300 mOsm, 305 mOsm, 350 mOsm, 405 mOsm, and 470 mOsm.

[0042] According to an embodiment of the present invention, the fluticasone furoate micelle solution comprises, by weight percentage, the following raw and auxiliary materials:

[0043] 0.005%-1.5wt% (e.g., 0.015wt%, 0.05wt%, 0.08wt%) of fluticasone furoate;

[0044] 0.05%-1.5wt% (e.g., 0.3wt%, 1.0wt%, 1.5wt%) of lipophilic components (e.g., Span 85, short-chain / medium-chain / long-chain fatty acid triesters, DPPC, HSPC, DOPC, egg yolk lecithin, soy lecithin);

[0045] 1.0%-20.0wt% (e.g., 2.4wt%, 10.0wt%) of nonionic surfactants (e.g., HS-15, polyethylene glycol succinate, polysorbate 80);

[0046] 0.05%-1.0wt% (e.g., 0.2wt%) of pH adjuster (e.g., disodium hydrogen phosphate);

[0047] 0.1%-2.0wt% (e.g., 0.6wt%) of osmotic pressure regulators (e.g., sodium chloride, propylene glycol);

[0048] 0.01%-0.1wt% (e.g., 0.02wt%) of a chelating agent (e.g., disodium edetate);

[0049] 0.01%-0.5wt% (e.g., 0.2wt%) of antibacterial agent (e.g., potassium sorbate);

[0050] The remainder is water.

[0051] According to some embodiments of the present invention, the fluticasone furoate micelle solution can be formulated into inhaler and nasal spray forms, including inhalation aerosols, inhalation sprays, nebulized inhalation solutions, nasal sprays, dual-power nasal sprays, and can also be formulated into eye drops, topical drug delivery formulations, etc.

[0052] This invention also provides a method for preparing the above-mentioned fluticasone furoate micelle solution, the preparation method comprising the following steps:

[0053] The lipophilic components, nonionic surfactants, and fluticasone furoate are dissolved, dried, and then water and other optional excipients are added.

[0054] According to an embodiment of the present invention, the preparation method specifically includes the following steps:

[0055] 1) Dissolve the lipophilic component, nonionic surfactant and fluticasone furoate in a solvent to obtain solution-1;

[0056] 2) Remove the solvent from solution-1 and dry to obtain the sample;

[0057] 3) Add water and optional other excipients (such as pH adjusters, osmotic pressure adjusters, chelating agents, solubilizers, antibacterial agents, etc.) to the sample from step 2), dissolve, emulsify under high shear, homogenize, and filter to obtain the solution.

[0058] According to an embodiment of the present invention, in step 1), the solvent is selected from solvents capable of dissolving lipophilic components, nonionic surfactants and fluticasone furoate, such as anhydrous ethanol, dichloromethane, tert-butanol, ethyl acetate, etc.

[0059] According to an embodiment of the present invention, step 2) specifically involves: removing most of the solvent by a rotary evaporator, removing the residual solvent by a vacuum drying oven, and then drying.

[0060] According to an embodiment of the present invention, the parameters of the rotary evaporator are as follows: temperature 35℃-50℃ (e.g., 40℃), and evaporation time 15min-240min (e.g., 120min).

[0061] According to an embodiment of the present invention, the parameters of the vacuum drying oven are: temperature of 35℃-50℃ (e.g., 40℃) and drying time of 15min-240min (e.g., 180min).

[0062] According to an embodiment of the present invention, in step 3), the parameters for high-shear emulsification are: rotation speed 100rpm-20000rpm, duration 1min-30min.

[0063] According to an embodiment of the present invention, in step 3), the homogenization treatment is a microfluidic homogenization treatment; preferably, the microfluidic homogenization treatment conditions are 2000pa-25000pa, 2 cycles-20 cycles.

[0064] The present invention also provides the use of the above-mentioned fluticasone furoate micelle solution in the preparation of medicaments for the treatment and / or prevention of asthma and chronic obstructive pulmonary disease.

[0065] The present invention also provides the use of the above-mentioned fluticasone furoate micelle solution in the preparation of medicaments for the treatment and / or prevention of allergic rhinitis, nasal polyps, sinusitis, and perioperative recovery period anti-inflammatory treatment of nasal polyps and sinusitis.

[0066] The present invention also provides a fluticasone furoate micellar solution formulation, comprising the above-mentioned fluticasone furoate micellar solution and pharmaceutically acceptable suitable pharmaceutical excipients and matrix materials, wherein the pharmaceutical excipients and matrix materials are one or a combination of several of carbomer, sodium hyaluronate, xanthan gum, sodium carboxymethyl (propyl)cellulose, azone, glycerol, propylene glycol, sodium hydroxide, preservatives, etc., wherein fluticasone furoate accounts for 0.015%-50 wt% by weight, and other excipients and matrix materials account for 50%-99.985 wt%.

[0067] The present invention also provides the use of the above-mentioned fluticasone furoate micelle solution formulation in the preparation of medicaments for the treatment and / or prevention of dermatitis, acute urticaria, chronic eczema, neurodermatitis, atopic dermatitis, erythematous squamous skin diseases such as psoriasis, vitiligo, alopecia areata, cutaneous vasculitis, non-infectious granulomas, cutaneous lymphocytic infiltration, proliferative scars, cutaneous T-cell lymphoma, and autoimmune diseases such as bullous pemphigoid.

[0068] The present invention also provides a fluticasone furoate micellar solution formulation, comprising the above-mentioned fluticasone furoate micellar solution and pharmaceutically acceptable suitable pharmaceutical excipients and matrix materials, wherein the pharmaceutical excipients and matrix materials are one or more combinations of chitosan, alginate, sodium hyaluronate, glycerin, propylene glycol, preservatives, etc., wherein fluticasone furoate accounts for 0.015%-50 wt% by weight, and other excipients and matrix materials account for 50%-99.985 wt%.

[0069] The present invention also provides the use of the above-mentioned fluticasone furoate micelle solution formulation in the preparation of medicaments for the treatment and / or prevention of ocular diseases such as trachoma, conjunctivitis, keratitis, episcleritis, uveitis, orbital cellulitis, and endophthalmitis.

[0070] The beneficial effects of this invention are:

[0071] This invention provides a solution of fluticasone furoate in micelle form, wherein the solubility of fluticasone furoate in water is increased to 0.015 mg / g-0.8 mg / g. The micelles in the solution are uniform in size, stable in aqueous solution, and can be stored for extended periods. Furthermore, when administered as an inhalant, the percentage of fine particles in the aerodynamic particle size of the solution is higher than 40%, with most droplets depositing into the lungs.

[0072] The method for preparing micelle solutions provided by this invention is simple and easy to industrialize. The particle size can be changed by the process to prepare nano micelles with a particle size controllable between 100 nm and 10 μm.

[0073] The micellar solution provided by this invention has high solubility of the active ingredient fluticasone furoate, and exhibits good dissolution and absorption rates on the nasal mucosa and alveolar mucosa. Therefore, while achieving the same therapeutic effect, the dosage can be further reduced, thereby reducing toxic side effects.

[0074] This invention provides micelles encapsulating fluticasone furoate and micelle formulations exhibiting high size uniformity, higher drug loading, and high encapsulation efficiency. The micelles disclosed herein are particularly suitable for nebulized inhalation and provide better pulmonary deposition, and are especially suitable for nasal administration to reduce dosage and improve bioavailability. Attached Figure Description

[0075] Figure 1 An optical microscope image of the precipitated crystals of micelles from Formulation 1 of Example 1 is shown.

[0076] Figure 2 Transmission electron microscopy images of micelles from Formulation 18 of Example 2 are shown. Detailed Implementation

[0077] The present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0078] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0079] The specific embodiments involve the following testing equipment and methods:

[0080] Characteristics: Visually

[0081] pH value: pH meter

[0082] Osmotic pressure: Freezing point osmometer

[0083] Content, delivery dose, related substances, encapsulation efficiency, drug loading: High performance liquid chromatography

[0084] Micellar particle size distribution: Malvern nanoparticle size analyzer

[0085] Transmission electron microscope image: Transmission electron microscope

[0086] Optical microscope image: Optical microscope

[0087] Spray particle size distribution: NeoPatek laser particle size analyzer

[0088] Spray patterns and spray geometry: Spray View

[0089] Aerodynamic particle size distribution: Anderson 8th stage impactor

[0090] When used in this document, the terms "D10, D50, D90, FPF" refer to:

[0091] D10 refers to the particle size corresponding to a sample when the cumulative particle size distribution number reaches 10%, and the unit is micrometer or nanometer.

[0092] D50 refers to the particle size at which the cumulative particle size distribution number of a sample reaches 50%, and the unit is micrometer or nanometer.

[0093] D90 refers to the particle size at which the cumulative particle size distribution of a sample reaches 90%, measured in micrometers or nanometers.

[0094] FPF refers to the percentage of the total delivered dose from samples with an aerodynamic particle size distribution smaller than 5 micrometers, i.e., the percentage of fine particle dose, expressed in units of 0.5 μm.

[0095] Example 1

[0096] Comparative Example 1

[0097] Prescription a:

[0098]

[0099] b process:

[0100] 1. Weigh the prescribed amount of lipophilic ingredients or nonionic surfactants and fluticasone furoate into a brown eggplant-shaped flask, add 50g of anhydrous ethanol, dissolve at 40°C for 10 minutes, after complete dissolution, remove the ethanol by rotary evaporation at 40°C for 120 minutes, and then vacuum dry in a vacuum drying oven at 40°C for 180 minutes.

[0101] 2. Weigh the prescribed amounts of disodium hydrogen phosphate, sodium chloride, disodium edetate, and purified water and add them to the sample after solvent recovery. Shake and dissolve the sample on a shaker for 10 minutes, emulsify under high shear at 6000 rpm for 10 minutes, homogenize under microfluidic pressure at 20000 Pa for 2 cycles, filter, and fill into low-density polyethylene bottles to obtain the final product.

[0102] c. Result:

[0103]

[0104]

[0105] The results above show that when only one lipophilic component or one surfactant is added, the fluticasone furoate micelles are unstable. Crystals precipitate after being left at room temperature overnight and after being left at room temperature for one week, respectively. The content of the supernatant decreases significantly, and the micelle size distribution of the supernatant increases significantly, making the micelle system unstable.

[0106] Comparative Example 2

[0107] Prescription a:

[0108]

[0109] b process:

[0110] 1. Weigh the prescribed amount of lipophilic ingredients or nonionic surfactants and fluticasone furoate into a brown eggplant-shaped flask, add 50g of anhydrous ethanol, dissolve at 40°C for 10 minutes, after complete dissolution, remove the ethanol by rotary evaporation at 40°C for 120 minutes, and then vacuum dry in a vacuum drying oven at 40°C for 180 minutes.

[0111] 2. Weigh the prescribed amounts of disodium hydrogen phosphate, sodium chloride, disodium edetate, and purified water and add them to the sample after solvent recovery. Shake and dissolve the sample on a shaker for 10 minutes, emulsify under high shear at 6000 rpm for 10 minutes, homogenize under microfluidic pressure at 20000 Pa for 2 cycles, filter, and fill into low-density polyethylene bottles to obtain the final product.

[0112] c. Result:

[0113]

[0114]

[0115] The results above show that when only one lipophilic component or nonionic surfactant is added, and the amount of the single lipophilic component or surfactant is increased to 2.7%, the fluticasone furoate micelles are unstable. Crystals precipitate after being placed at room temperature for three days and one week, respectively. The content of the supernatant decreases significantly, and the micelle size distribution of the supernatant increases significantly, making the micelle system unstable.

[0116] Comparative Example 3

[0117] Prescription a:

[0118]

[0119] b process:

[0120] Under a water bath at 65°C, each nonionic surfactant was heated and melted in a beaker for about 30 minutes. Purified water was added to a volume of 50g, and the mixture was sheared and mixed using a high-shear mixer. The prescribed amount of fluticasone furoate was added, and the mixture was sheared and mixed using a high-shear mixer at 1000 rpm for about 7 minutes. The mixture was then filtered and bottled into low-density polyethylene bottles to obtain the final product.

[0121] c. Result:

[0122]

[0123] The samples prepared by the ratio of fluticasone furoate to the above-mentioned nonionic surfactant were all white suspensions, and crystal precipitates appeared after standing for 1 day, indicating that the formulation process is not suitable for the preparation of fluticasone furoate micelles.

[0124] Comparative Example 4

[0125] Prescription a:

[0126]

[0127]

[0128] b process:

[0129] 1. Weigh the prescribed amount of lipophilic ingredients or nonionic surfactants and fluticasone furoate into a brown eggplant-shaped flask, add 50g of anhydrous ethanol, dissolve at 40°C for 10 minutes, after complete dissolution, remove the ethanol by rotary evaporation at 40°C for 120 minutes, and then vacuum dry in a vacuum drying oven at 40°C for 180 minutes.

[0130] 2. Weigh the prescribed amounts of disodium hydrogen phosphate, sodium chloride, disodium edetate, and purified water and add them to the sample after solvent recovery. Shake and dissolve the sample on a shaker for 10 minutes, emulsify under high shear at 6000 rpm for 10 minutes, homogenize under microfluidic pressure at 20000 Pa for 2 cycles, filter, and fill into low-density polyethylene bottles to obtain the final product.

[0131] c. Result:

[0132]

[0133] The results above show that when only one lipophilic component or nonionic surfactant is added, and the amount of the single lipophilic component or surfactant continues to increase to 6.0%, the fluticasone furoate micelles are still unstable. Crystals precipitate after being placed at room temperature for three days and one week, respectively. The content of the supernatant decreases significantly, and the micelle size distribution of the supernatant increases significantly, making the micelle system unstable.

[0134] Comparative Example 5

[0135] Prescription a:

[0136]

[0137]

[0138] b process:

[0139] (1) Weigh out the prescribed amounts of fluticasone furoate, egg yolk lecithin, sodium taurine, sodium glycocholate, sodium glycodeoxycholate, sodium taurine deoxycholate, sodium glycodeoxycholate, sodium glycochenodeoxycholate, and sodium taurine deoxycholate, and place them in a 500ml round-bottom flask. Add an appropriate amount of anhydrous ethanol to dissolve them completely.

[0140] (2) The ethanol mixture obtained in (1) is subjected to rotary evaporation on a rotary evaporator until the ethanol solution is completely evaporated and a uniform thin film is formed in the system.

[0141] (3) Add water for injection into the membrane and gently shake it under ultrasonic conditions in a water bath to hydrate it.

[0142] c. Result:

[0143]

[0144] The fluticasone furoate solution prepared by the above formula did not dissolve during hydration and was a white suspension. After standing for 1 day, crystal precipitates were formed in all of them, indicating that the formula process is not suitable for the preparation of fluticasone furoate micelles.

[0145] Example 2

[0146] Prescription a:

[0147]

[0148] b process:

[0149] 1. Weigh the prescribed amounts of Span 85, polysorbate 80, and fluticasone furoate into a brown eggplant-shaped flask, add 50g of anhydrous ethanol, dissolve at 40°C for 10 minutes, and after complete dissolution, remove the ethanol by rotary evaporation at 40°C for 120 minutes, and then vacuum dry in a vacuum drying oven at 40°C for 180 minutes.

[0150] 2. Weigh the prescribed amounts of disodium hydrogen phosphate, sodium chloride, disodium edetate, and purified water and add them to the sample after solvent recovery. Shake and dissolve the sample on a shaker for 10 minutes, emulsify under high shear at 6000 rpm for 10 minutes, homogenize under microfluidic pressure at 20000 Pa for 2 cycles, filter, and fill into low-density polyethylene bottles to obtain the final product.

[0151] c. Result:

[0152]

[0153] The stability data of fluticasone furoate micelle solutions above show that adjusting the formulation and adding the lipophilic component Span 85 and the nonionic surfactant polysorbate 80 as surfactants resulted in an unexpectedly stable fluticasone furoate micelle system. In accelerated testing (40℃ / 75%RH) and long-term testing (25℃ / 60%RH) for 30 days, the properties, pH, and osmotic pressure of the fluticasone furoate micelles remained stable and controllable. Their content, related substances, encapsulation efficiency, drug loading, and viscosity also remained stable and controllable. Their in vitro formulation characteristics, such as micelle size distribution and aerodynamic particle size distribution, also remained essentially unchanged. This indicates that the quality of the fluticasone furoate micelle solution is stable and controllable after using the two surfactants together. The aerodynamic particle size distribution results show that the fine particle dose percentage (FPF) is above 40%, indicating a high lung deposition rate.

[0154] Example 3

[0155] Prescription a:

[0156]

[0157] b process:

[0158] 1. Weigh the prescribed amounts of egg yolk lecithin, vitamin E succinate polyethylene glycol ester, and fluticasone furoate into a brown eggplant-shaped flask. Add 50g of anhydrous ethanol and dissolve at 40°C for 10 minutes. After complete dissolution, remove the ethanol by rotary evaporation at 40°C for 120 minutes. Then, vacuum dry in a vacuum drying oven at 40°C for 180 minutes.

[0159] 2. Weigh the prescribed amounts of disodium hydrogen phosphate, sodium chloride, disodium edetate, and purified water and add them to the sample after solvent recovery. Shake and dissolve the sample on a shaker for 10 minutes, emulsify under high shear at 6000 rpm for 10 minutes, homogenize under microfluidic pressure at 20000 Pa for 2 cycles, filter, and fill into low-density polyethylene bottles to obtain the final product.

[0160] c. Result:

[0161]

[0162] The results above show that, based on Example 2, by replacing the lipophilic component Span 85 with the lipophilic component egg yolk lecithin, and the nonionic surfactant polysorbate 80 with the nonionic surfactant vitamin E succinate polyethylene glycol ester, while keeping the rest of the formulation and process consistent with Example 2, the properties, pH value, osmotic pressure, content, related substances, encapsulation efficiency, drug loading, viscosity, and aerodynamic particle size distribution of the prepared fluticasone furoate micelle solution all meet the requirements.

[0163] Example 4

[0164] Prescription a:

[0165]

[0166] b process:

[0167] 1. Weigh the prescribed amounts of egg yolk lecithin, vitamin E succinate polyethylene glycol ester, and fluticasone furoate into a brown eggplant-shaped flask. Add 50g of anhydrous ethanol and dissolve at 40°C for 10 minutes. After complete dissolution, remove the ethanol by rotary evaporation at 40°C for 120 minutes. Then, vacuum dry in a vacuum drying oven at 40°C for 180 minutes.

[0168] 2. Weigh the prescribed amounts of disodium hydrogen phosphate, sodium chloride, disodium edetate, and purified water and add them to the sample after solvent recovery. Shake and dissolve the sample on a shaker for 10 minutes, emulsify under high shear at 6000 rpm for 10 minutes, homogenize under microfluidic pressure at 20000 Pa for 2 cycles, filter, and fill into low-density polyethylene bottles to obtain the final product.

[0169] c. Result:

[0170]

[0171] The results above show that, based on Example 3, by increasing the amount of polyethylene glycol succinate (VES) to 5.7%, while keeping the rest of the formulation and process consistent with Example 3, the properties, pH value, osmotic pressure, content, related substances, encapsulation efficiency, drug loading, viscosity, and aerodynamic particle size distribution of the prepared fluticasone furoate micelle solution all meet the requirements.

[0172] Example 5

[0173] Prescription a:

[0174]

[0175] b process:

[0176] 1. Weigh the prescribed amount of lipophilic components, nonionic surfactants, and fluticasone furoate into a brown eggplant-shaped flask, add 50g of anhydrous ethanol, dissolve at 40°C for 10 minutes, and after complete dissolution, remove the ethanol by rotary evaporation at 40°C for 120 minutes, and then vacuum dry in a vacuum drying oven at 40°C for 180 minutes.

[0177] 2. Weigh the prescribed amounts of disodium hydrogen phosphate, sodium chloride, disodium edetate, and purified water and add them to the sample after solvent recovery. Shake and dissolve the sample on a shaker for 10 minutes, emulsify under high shear at 6000 rpm for 10 minutes, homogenize under microfluidic pressure at 20000 Pa for 2 cycles, filter, and fill into low-density polyethylene bottles to obtain the final product.

[0178] c. Result:

[0179]

[0180] The comparison results of prescriptions 18, 21, 22, and 23 above show that, based on prescriptions 18 and 21, after adjusting the types of lipophilic components and nonionic surfactants, the properties, pH value, osmotic pressure, content, related substances, encapsulation efficiency, drug loading, viscosity, and aerodynamic particle size distribution of the fluticasone furoate micelle solutions prepared by prescriptions 22 and 23 did not change significantly and all met the requirements.

[0181] Example 6

[0182] Prescription a:

[0183]

[0184] b process:

[0185] 1. Weigh the prescribed amounts of medium-chain triglycerides, polyethylene glycol succinate, and fluticasone furoate into a brown eggplant-shaped flask. Add 100g of anhydrous ethanol and dissolve at 40°C for 10 minutes. After complete dissolution, remove the ethanol by rotary evaporation at 40°C for 120 minutes. Then, vacuum dry in a vacuum drying oven at 40°C for 180 minutes.

[0186] 2. Weigh the prescribed amounts of propylene glycol, potassium sorbate, disodium edetate, and purified water and add them to the sample after solvent recovery. Shake and dissolve the sample on a shaker for 10 minutes, emulsify under high shear at 6000 rpm for 10 minutes, homogenize under microfluidic pressure at 20000 Pa for 2 cycles, filter, and fill into nasal spray bottle to obtain the final product.

[0187] c. Result:

[0188]

[0189] The results above show that by replacing the lipophilic component with medium-chain triglycerides at a dosage of 1%, increasing the dosage of polyethylene glycol succinate (VES) to 10%, and maintaining the same formulation and process as in Example 3, the prepared fluticasone furoate micelle solution, when filled into a nasal spray device, meets the requirements in terms of appearance, pH, osmotic pressure, content, related substances, encapsulation efficiency, drug loading, viscosity, micelle size distribution, spray particle size distribution, spray pattern, spray geometry, and aerodynamic particle size distribution.

[0190] Example 7

[0191] Prescription a:

[0192]

[0193]

[0194] b process:

[0195] 1. Weigh the prescribed amounts of medium-chain triglycerides, polyethylene glycol succinate, and fluticasone furoate into a brown eggplant-shaped flask. Add 100g of anhydrous ethanol and dissolve at 40°C for 10 minutes. After complete dissolution, remove the ethanol by rotary evaporation at 40°C for 120 minutes. Then, vacuum dry in a vacuum drying oven at 40°C for 180 minutes.

[0196] 2. Weigh the prescribed amounts of propylene glycol, potassium sorbate, disodium edetate, and purified water and add them to the sample after solvent recovery. Shake and dissolve the sample on a shaker for 10 minutes, emulsify under high shear at 6000 rpm for 10 minutes, homogenize under microfluidic pressure at 20000 Pa for 2 cycles, filter, and fill into nasal spray bottle to obtain the final product.

[0197] c. Result:

[0198]

[0199] The results above show that by replacing the lipophilic component with medium-chain triglycerides at a dosage of 1.5%, increasing the dosage of polyethylene glycol succinate (VES) to 10%, and maintaining the same formulation and process as in Example 3, the prepared fluticasone furoate micelle solution, when filled into a nasal spray device, meets the requirements in terms of appearance, pH value, osmotic pressure, content, related substances, encapsulation efficiency, drug loading, viscosity, micelle size distribution, spray particle size distribution, spray pattern, spray geometry, and aerodynamic particle size distribution.

[0200] Example 8

[0201] Based on the fluticasone furoate micelle solution of the present invention, carbomer and glycerin are added to prepare a topical skin gel formulation.

[0202] Prescription a:

[0203]

[0204] b process:

[0205] 1. Weigh the prescribed amounts of egg yolk lecithin, vitamin E succinate polyethylene glycol ester, and fluticasone furoate into a brown eggplant-shaped flask. Add 50g of anhydrous ethanol and dissolve at 40°C for 10 minutes. After complete dissolution, remove the ethanol by rotary evaporation at 40°C for 120 minutes. Then, vacuum dry in a vacuum drying oven at 40°C for 180 minutes.

[0206] 2. Weigh the prescribed amounts of disodium hydrogen phosphate, sodium chloride, disodium edetate, and purified water and add them to the sample after solvent recovery. Shake and dissolve the sample on a shaker for 10 minutes, emulsify under high shear at 6000 rpm for 10 minutes, homogenize under microfluidic pressure at 20000 Pa for 2 cycles, filter, and set aside.

[0207] 3. Weigh the prescribed amounts of carbomer 940 and glycerin into the solution from step 2, and stir with an electric stirrer at 1000 rpm for 30 minutes to obtain the final product.

[0208] c. Result:

[0209]

[0210] The results above show that, based on Example 3, after adding 0.5% carbomer 940 and 2% glycerol to the prepared fluticasone furoate micelle solution, while keeping the rest of the formulation and process consistent with Example 3, the properties, content, and related substances of the prepared fluticasone furoate gel all meet the requirements.

[0211] Example 9

[0212] Based on the fluticasone furoate micelle solution of the present invention, sodium hyaluronate and benzalkonium chloride are added to prepare an eye drop formulation.

[0213] Prescription a:

[0214]

[0215] b process:

[0216] 1. Weigh the prescribed amounts of egg yolk lecithin, vitamin E succinate polyethylene glycol ester, and fluticasone furoate into a brown eggplant-shaped flask. Add 50g of anhydrous ethanol and dissolve at 40°C for 10 minutes. After complete dissolution, remove the ethanol by rotary evaporation at 40°C for 120 minutes. Then, vacuum dry in a vacuum drying oven at 40°C for 180 minutes.

[0217] 2. Weigh the prescribed amounts of disodium hydrogen phosphate, sodium chloride, disodium edetate, and purified water and add them to the sample after solvent recovery. Shake and dissolve the sample on a shaker for 10 minutes, emulsify under high shear at 6000 rpm for 10 minutes, homogenize under microfluidic pressure at 20000 Pa for 2 cycles, filter, and set aside.

[0218] 3. Weigh the prescribed amounts of sodium hyaluronate and benzalkonium chloride into the solution from step 2, and stir with an electric stirrer at 1000 rpm for 30 minutes to obtain the final product.

[0219] c. Result:

[0220] The results above show that, based on Example 3, after adding 0.1% sodium hyaluronate and 0.02% benzalkonium chloride to the prepared fluticasone furoate micelle solution, while keeping the rest of the formulation and process consistent with Example 3, the properties, content, and related substances of the prepared fluticasone furoate eye drops all meet the requirements.

[0221]

[0222] Example 10

[0223] Pharmacodynamic study of fluticasone furoate inhalation solution for the treatment of bronchial asthma

[0224] Experimental objective:

[0225] This study established a rat model of bronchial asthma using egg white albumin. After treatment with fluticasone furoate inhalation solution (prescription sample from Example 2) via oral and nasal inhalation, the effects of fluticasone furoate inhalation solution on lung function, lung pathology, and changes in white blood cell and eosinophil counts were observed. Commercially available budesonide inhalation suspension (trade name: Pulmicort, specification 2ml:1mg, purchased from Guangzhou Youwa Technology Co., Ltd.) and a self-made fluticasone furoate inhalation suspension (0.02wt% polysorbate 80 and 10wt% of the prescribed volume of purified water were mixed thoroughly and the original volume was added) were used. 0.05 wt% fluticasone furoate was emulsified under high shear at 6000 rpm for 10 minutes to obtain a concentrated solution. 0.85 wt% sodium chloride, 0.028 wt% anhydrous citric acid, 0.05 wt% sodium citrate, and 0.01 wt% disodium edetate were dissolved in 50 wt% of the prescribed volume of purified water. This solution was combined with the concentrated fluticasone furoate solution, and purified water was added to bring the total prescribed volume to a final volume. The mixture was then emulsified under high shear at 6000 rpm for 30 minutes to obtain the final solution. This solution served as a control to evaluate the efficacy of fluticasone furoate inhalation solution for bronchial asthma, providing experimental evidence for clinical application.

[0226] b. Experimental method:

[0227] Ninety-six qualified SPF-grade SD rats, half male and half female, were randomly divided into a normal control group (n=16) and a model group (n=80). The model group rats were sensitized by intraperitoneal injection of 0.5 mL / rat of 4% egg white albumin (OVA) and 0.5 mL / rat of 2% Al(OH)3, once a week for two weeks. The normal control group rats received only an intraperitoneal injection of 0.5 mL / rat of 2% Al(OH)3. On day 15 of sensitization, the model rats were placed in a small animal oral-nasal exposure system, and challenged with 2% egg white albumin solution nebulized and inhaled as aerosol at 20 g / cm³ for 30 minutes, once a week for three weeks, to induce asthma attacks. The successful model was confirmed by the appearance of symptoms such as rapid breathing, abdominal muscle spasms, and agitation after the challenge. Rats in the model group were randomly divided into 5 groups according to body weight: model control group, budesonide inhalation suspension group (0.090 mg / kg), fluticasone furoate inhalation suspension group (0.090 mg / kg), and low- and high-dose fluticasone furoate inhalation solution groups (0.045 mg / kg and 0.090 mg / kg, respectively). Each group consisted of 16 animals, half male and half female. All groups received the corresponding aerosol concentration via oral and nasal inhalation. The normal control group and model control group received 0.9% sodium chloride injection via oral and nasal inhalation for the same duration as the high-dose fluticasone furoate inhalation solution group, twice daily, with a 4-hour interval between morning and afternoon administration, for 7 consecutive days. Aerosol content and particle size of the test substance were analyzed at the first and last administrations. On the day after the last administration, six animals were randomly selected from each group to detect changes in airway resistance (Penh), peak inspiratory flow rate (PIF), and peak flow rate (PEF) before and after acetylcholine (ACh) stimulation. After the pulmonary function test, bronchoalveolar lavage fluid (BALF) was collected to detect white blood cell (WBC) and eosinophil (Eos) levels. On the day after the last administration (6 rats / group) and one week after the last administration (4 rats / group), the trachea, bronchi, and lungs of rats were collected, fixed, embedded in paraffin, sectioned, and stained with hematoxylin and eosin (HE) to observe the histopathological examination of the trachea, bronchi, and lungs.

[0228] c. Experimental results:

[0229] ① Test Substance Analysis: Particle size analysis was performed on the first and last days of administration for the low- and high-dose fluticasone furoate inhalation solution, fluticasone furoate suspension for inhalation, and budesonide suspension for inhalation. Results showed that the median aerodynamic mass diameter (MMAD) of fluticasone furoate and budesonide inhalation solutions at all concentrations was within 1–4 μm before the first and last administration, and the geometric standard deviation (GSD) was within 1–3, meeting the experimental requirements. High-performance liquid chromatography (HPLC) analysis was also performed on the first and last days of administration for the aerosol particles in the low- and high-dose fluticasone furoate inhalation solution, fluticasone furoate suspension for inhalation, and budesonide suspension for inhalation. Results showed that the concentration deviation of the aerosol in the low- and high-dose fluticasone furoate inhalation solution, fluticasone furoate suspension for inhalation, and budesonide suspension for inhalation was less than ±20%, meeting the experimental requirements. The test substances fluticasone furoate and budesonide were not detected in the aerosol particles of both the normal control group and the model control group.

[0230] Table 1. Analysis of aerosol content

[0231]

[0232]

[0233] Table 2 Particle size analysis of aerosols

[0234]

[0235] ② Effects on lung function: Low and high doses of fluticasone furoate inhalation solution, fluticasone furoate suspension, and budesonide suspension significantly increased pre-Ach challenge level (PIF) in model rats. High doses of fluticasone furoate inhalation solution significantly increased post-Ach challenge level (PEF) and decreased Penh level in model rats.

[0236] Table 3 Effects of fluticasone furoate inhalation solution on lung function in model rats ( n=6)

[0237]

[0238] Note: Compared with the normal control group + P≤0.05, ++ P≤0.01; compared with the model control group ** P≤0.01.

[0239] Table 4. Effects of fluticasone furoate inhalation solution on lung function in model rats (after Ach challenge). n=6)

[0240]

[0241] Note: Compared with the normal control group + P≤0.05, ++ P≤0.01; compared with the model control group * P≤0.05.

[0242] ③ Effects on white blood cells (WBC) and eosinophils (Eos) in BALF: Low and high doses of fluticasone furoate inhalation solution, fluticasone furoate suspension for inhalation, and budesonide suspension for inhalation can significantly reduce the WBC and Eos content in the BALF of model rats.

[0243] Table 5. Effects of fluticasone furoate inhalation solution on WBC and Eos in BALF of model rats ( n=6)

[0244]

[0245] Note: Compared with the normal control group ++ P≤0.01; compared with the model control group * P≤0.05, ** P≤0.01.

[0246] ④ Histopathological examination: On the day following the last administration, high-dose fluticasone furoate inhalation solution, fluticasone furoate inhalation suspension, and budesonide inhalation suspension significantly reduced lung tissue pathological scores. One week after the last administration, low-dose and high-dose fluticasone furoate inhalation solution and budesonide inhalation suspension significantly reduced lung tissue pathological scores.

[0247] Table 6. Effects of fluticasone furoate inhalation solution on lung tissue scores in model rats ( n=6)

[0248]

[0249] Note: Compared with the normal control group ++ P≤0.01; compared with the model control group * P≤0.05.

[0250] d. Experimental conclusion:

[0251] Under the conditions of this experiment, fluticasone furoate inhalation solution significantly reduced WBC and Eos levels in the BALF of model rats, improved lung function and the degree of lung and bronchiolar lesions, suggesting that fluticasone furoate inhalation solution has a significant therapeutic effect on bronchial asthma model rats. Moreover, at the same dose, fluticasone furoate inhalation solution is more effective than fluticasone furoate inhalation suspension and budesonide inhalation suspension. The effective dose of fluticasone furoate inhalation solution is the low dose (0.045 mg / kg).

[0252] Example 11

[0253] Pharmacokinetic study of fluticasone furoate micelle nasal spray solution

[0254] Experimental objective:

[0255] This study used SD rats to administer different doses of fluticasone furoate micelle nasal spray solution (Formulation process sample of Example 6) via a single intranasal administration in parallel. Plasma samples were collected at different time points to detect the blood concentration of fluticasone furoate at different time points, and the main pharmacokinetic parameters were calculated to investigate the pharmacokinetic characteristics of the drug in animals, providing a reference for subsequent pharmacodynamic experiments.

[0256] b. Experimental method:

[0257] Test substance and reference standard:

[0258]

[0259] *Note: The original formulation 1, brand name Wenshi, specification 27.5μg per spray, was purchased from Zhejiang Huiren Pharmaceutical Chain Co., Ltd.

[0260] Twenty SD rats, weighing 200g-250g, with half males and half females, were randomly divided into 5 groups according to body weight, with 4 rats in each group and half males and half females. The grouping information is as follows:

[0261]

[0262]

[0263] The dosage design for each group is as follows:

[0264]

[0265] Note: The administration method is nasal drops.

[0266] c. Experimental results:

[0267] The main pharmacokinetic parameters of plasma fluticasone furoate after a single intranasal administration of different doses of fluticasone furoate micelle nasal spray to SD rats.

[0268]

[0269]

[0270] Note: *The drug content in the plasma of the original formulation group 1 (13.69 μg / animal; fluticasone furoate) was below the lower limit of quantification.

[0271] d. Experimental conclusion:

[0272] In SD rats, the plasma drug content of the original formulation 1 (13.69 μg / rat; fluticasone furoate) after a single nasal administration was below the lower limit of quantification. This indicates that the original formulation 1 of fluticasone furoate nasal spray is a suspension, which greatly affects its dissolution and absorption rates, resulting in a high dosage, slow onset of action, and low absolute bioavailability. In contrast, the drug content in the plasma of the self-developed formulation 2 (13.87 μg / rat; fluticasone furoate) was detectable within the normal range. This indicates that the self-developed formulation 2 of fluticasone furoate nasal spray is a micellar solution, which is rapidly absorbed, has a rapid onset of action, and high absolute bioavailability.

[0273] Example 12

[0274] Pharmacodynamic study of fluticasone furoate micelle nasal spray solution

[0275] Experimental objective:

[0276] This study used SPF-grade BALB / c mice to establish an allergic rhinitis animal model. The same dose of fluticasone furoate micelle nasal spray solution (Formulation process sample of Example 6) and fluticasone furoate nasal spray (Original Formulation 1 of Example 11) were administered nasally for 7 consecutive days. Behavioral symptom scores (nasal itching, sneezing, rhinorrhea) and nasal mucosal tissue morphology were observed to investigate the efficacy of the drugs in the allergic rhinitis model animals.

[0277] b. Experimental method:

[0278] One hundred and thirty qualified SPF-grade BALB / c mice, weighing 18–22 g, were selected and divided into a normal control group (n=10) and a model control group (n=30). An allergic rhinitis model was established in the model group. Sensitization was first performed using OVA solution prepared with 0.4% aluminum hydroxide gel at a concentration of 0.2 mg·mL⁻¹. 0.05 mL was injected subcutaneously into the two hind paws, both groins, and two points on the back, and 0.2 mL was injected intraperitoneally. On days 7, 14, and 21, 0.5 mL of OVA solution was injected intraperitoneally. The normal control group received an equal volume of 0.9% sodium chloride injection intraperitoneally. Challenge: On day 22, the model group received 2 mL of OVA solution via nasal drops. 5 mg / ml ovalbumin powder solution, 20 μl / side, bilateral administration, once daily in the morning, for 14 consecutive days; after challenge on day 29, observe the abnormality of the mouse nose within 30 minutes, and use superimposed quantitative scoring, the total score is greater than 5 points to indicate successful modeling, the mouse behavioral symptom grading standard is shown in Table 1; selected animals with successful modeling were randomly divided into model control group, fluticasone furoate nasal spray group, and fluticasone furoate micelle nasal spray solution group, 10 animals in each group, each group of animals was given 25 μl / side of the corresponding drug, bilateral administration, once daily in the afternoon, for 7 consecutive days, the normal control group and the model control group were given the same volume of CZ002 nasal spray blank excipient. Behavioral symptom scores (nasal itching, sneezing, and runny nose) were assessed in each group of animals before administration, and 3 and 7 days after administration. On the day following the last administration, each group of animals was euthanized by cervical dislocation, and nasal mucosa tissue was dissected, placed in 10% neutral formalin solution, sectioned, embedded, and stained with hematoxylin and eosin (HE) to observe morphological changes in the nasal mucosa tissue.

[0279] c. Experimental results:

[0280] ① Impact on behavioral symptom scores

[0281] As shown in Table 7, compared with the model control group, the behavioral symptom scores of mice in the fluticasone furoate nasal spray group and the fluticasone furoate micelle nasal spray solution group were significantly reduced on D3 and D7 after administration (P≤0.01 or P≤0.05). Compared with the fluticasone furoate nasal spray group, the behavioral symptom scores of mice in the fluticasone furoate micelle nasal spray solution group were significantly reduced on D3 after administration (P≤0.01 or P≤0.05).

[0282] Table 7. Effects of fluticasone furoate micelle nasal spray on behavioral symptom scores in allergic rhinitis model mice. n=10)

[0283]

[0284] Note: Compared with the model control group ++ P≤0.01, +P≤0.05; compared with the fluticasone furoate nasal spray group ** P≤0.01, * P≤0.05.

[0285] ② Effects on morphological changes of nasal mucosa tissue

[0286] As shown in Table 8, compared with the normal control group, the animals in the model control group showed varying degrees of disordered nasal mucosal epithelial arrangement, ciliary loss, mucosal vasodilation, mucosal edema, and inflammatory cell infiltration mainly composed of eosinophils. The nasal mucosal tissue lesions of animals in each treatment group were improved to a certain extent after nasal administration. Compared with the normal control group, the pathological score of nasal mucosal tissue of animals in the model control group was significantly increased (P≤0.01). Compared with the model control group, the pathological score of nasal mucosal tissue of animals in the fluticasone furoate nasal spray group and the fluticasone furoate micelle nasal spray solution group was significantly decreased (P≤0.01).

[0287] Table 8. Effects of fluticasone furoate micelle nasal spray solution on histopathological scores of nasal mucosa in allergic rhinitis model mice. n=10)

[0288]

[0289] Note: Compared with the normal control group && P≤0.01; compared with the model control group ++ P≤0.01; compared with the fluticasone furoate nasal spray group * P≤0.05;

[0290] d. Experimental conclusion:

[0291] Under the experimental conditions, both the original fluticasone furoate nasal spray and the fluticasone furoate micelle nasal spray solution improved the behavioral symptoms (including sneezing, itching, and runny nose) in mice with allergic rhinitis and significantly improved the degree of nasal mucosal lesions. This suggests that both the original fluticasone furoate nasal spray and the fluticasone furoate micelle nasal spray solution have significant effects on allergic rhinitis. However, based on behavioral and histopathological scores, the fluticasone furoate micelle nasal spray solution is more effective than the original fluticasone furoate nasal spray.

[0292] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A fluticasone furoate micelle solution, characterized in that, The solution contains the following components: The solution contains 0.005%-1.5 wt% fluticasone furoate, 0.5%-20.0 wt% lipophilic components and nonionic surfactants, with the balance being water. The micelles are preferably nano micelles. The solution does not contain suspending agents, such as microcrystalline cellulose-sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, etc.

2. The fluticasone furoate micelle solution according to claim 1, characterized in that, The mass percentage of fluticasone furoate is 0.015%-1.0 wt%, for example, 0.015 wt%, 0.03 wt%, 0.05 wt%, 0.08 wt%, 0.1 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, and 0.9 wt%, and the sum of the mass percentages of the lipophilic component and the nonionic surfactant is 1.5%-11.5 wt%, for example, 1.5 wt%, 2.0 wt%, 2.5 wt%, 2.7 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 5.0 wt%, 8.0 wt%, 10.0 wt%, and 11.5 wt%.

3. The fluticasone furoate micelle solution according to claim 1, characterized in that, The lipophilic component is selected from one or more of Span (e.g., Span 85), DPPC, HSPC, DOPC, soybean lecithin, egg yolk lecithin, cholesterol, DSPE-PEG1000, and short-chain / medium-chain / long-chain fatty acid triesters. The nonionic surfactant is selected from one or more of polyethylene glycol succinate, HS-15, polyethylene glycol glycerol ester, polysorbate (e.g., polysorbate 80), and isopropyl myristate. The nonionic surfactant is preferably selected from the following combinations: a combination of short-chain / medium-chain / long-chain fatty acid triesters and polyethylene glycol succinate with vitamin E, a combination of egg yolk lecithin and polysorbate 80, a combination of soybean lecithin and polysorbate 80, a combination of Span 85 and polysorbate 80, a combination of DPPC and polysorbate 80, a combination of HSPC and HS-15, a combination of egg yolk lecithin and polyethylene glycol succinate with vitamin E, and a combination of soybean lecithin and polyethylene glycol succinate with vitamin E.

4. The fluticasone furoate micelle solution according to claim 2, characterized in that, The lipophilic component has a mass percentage of 0.05%-1.5 wt%, preferably 0.1%-1.5 wt%, for example 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 1.0 wt%, and 1.5 wt%. The nonionic surfactant has a mass percentage of 1.0%-19.95 wt%, preferably 2.0%-10.0 wt%, for example 2.0 wt%, 2.2 wt%, 2.4 wt%, 2.6 wt%, 2.8 wt%, 3.0 wt%, 4.0 wt%, 5.0 wt%, 6.0 wt%, 8.0 wt%, and 10.0 wt%. The mass ratio of the lipophilic component to the nonionic surfactant is 1:1-30, preferably 1:2-20, for example 1:4, 1:5, 1:6, 1:8, 1:10, 1:12, 1:15, 1:16, and 1:

18.

5. The fluticasone furoate micelle solution according to claim 1, characterized in that, The solution further includes pH adjusters, osmotic pressure adjusters, chelating agents, antibacterial agents, and solubilizers, wherein the pH value of the solution is 3.0-7.0, more preferably 3.5-7.0, for example 3.5, 4.0, 4.55, 4.6, 4.65, 4.7, 5.0, 6.0, 7.0; the osmotic pressure adjuster is selected from one or more of sodium chloride, potassium chloride, magnesium chloride, glucose, glycerol, propylene glycol, sorbitol, and mannitol; preferably, it is selected from one or more of sodium chloride, potassium chloride, magnesium chloride, and glucose; the chelating agent is selected from disodium edetate; the antibacterial agent is selected from benzalkonium chloride, potassium sorbate, benzyl alcohol, and phenethyl alcohol; and the solubilizer is selected from one or more of propylene glycol, glycerol, cyclodextrin, and PEG600.

6. The fluticasone furoate micelle solution according to claim 1, characterized in that, The encapsulation efficiency of the fluticasone furoate micelles is above 90%, for example 90.5%, 91.7%, 92.1%, 92.2%, 92.8%, 92.9%, 93%, 93.8%, 94.4%; the drug loading is 1.65%-2%, for example 1.68%, 1.69%, 1.7%, 1.71%, 1.72%, 1.73%, 1.76%, 1.78%, 1.86%; viscosity ( The mPa·s values ​​were 7.2–10, e.g., 7.2, 7.5, 7.7, 7.8, 7.9, 8.0, 8.1, 8.8, 8.9, 9.8; the aerodynamic particle size distribution (FPF) was 41–47%, e.g., 41.9%, 43.6%, 43.8%, 43.9%, 44%, 44.4%, 44.7%, 45%, 45.5%, 45.9%, 46.2%, 46.6%.

7. The fluticasone furoate micelle solution according to claim 1, characterized in that, The micelle size D10 of the fluticasone furoate solution is 5nm-100nm, preferably 10nm-80nm, such as 15nm, 30nm, 45nm, 50nm, 60nm, 65nm, and 70nm; the micelle size D50 of the fluticasone furoate solution is 100nm-1200nm, preferably 120nm-1100nm, such as 150nm, 200nm, 300nm, 400nm, and 500nm. The micelle size D90 of the fluticasone furoate solution is 400nm-3500nm, preferably 500nm-3400nm, such as 600nm, 1000nm, 1400nm, 1800nm, 2000nm, 2300nm, 2500nm, 2800nm, 3000nm, 3200nm, and 3300nm.

8. The fluticasone furoate micelle solution according to claim 1, characterized in that, The following raw and auxiliary materials are included by weight percentage: 0.005%-1.5wt% (e.g., 0.015wt%, 0.05wt%, 0.08wt%) of fluticasone furoate; 0.05%-1.5wt% (e.g., 0.3wt%, 1.0wt%, 1.5wt%) of lipophilic components (e.g., Span 85, short-chain / medium-chain / long-chain fatty acid triesters, DPPC, HSPC, DOPC, egg yolk lecithin, soy lecithin); 1.0%-20.0wt% (e.g., 2.4wt%, 10.0wt%) of nonionic surfactants (e.g., HS-15, polyethylene glycol succinate, polysorbate 80); 0.05%-1.0wt% (e.g., 0.2wt%) of pH adjuster (e.g., disodium hydrogen phosphate); 0.1%-2.0wt% (e.g., 0.6wt%) of osmotic pressure regulators (e.g., sodium chloride, propylene glycol); 0.01%-0.1wt% (e.g., 0.02wt%) of a chelating agent (e.g., disodium edetate); 0.01%-0.5wt% (e.g., 0.2wt%) of antibacterial agent (e.g., potassium sorbate); The remainder is water. The fluticasone furoate micelle solution can be formulated into inhaler and nasal spray forms, including inhalation aerosols, inhalation sprays, nebulized inhalation solutions, nasal sprays, dual-power nasal sprays, and can also be formulated into eye drops, topical drug delivery formulations, etc.

9. A method for preparing a fluticasone furoate micelle solution as described in claim 1, characterized in that, The preparation method includes the following steps: The lipophilic component, nonionic surfactant, and fluticasone furoate are dissolved in a solvent, dried, and then water and optional other excipients are added to dissolve and emulsify. The solvent is selected from those capable of dissolving the lipophilic component, nonionic surfactant, and fluticasone furoate, such as anhydrous ethanol, dichloromethane, tert-butanol, ethyl acetate, etc.

10. The use of the fluticasone furoate micelle solution of claim 1 in the preparation of a medicament for the treatment and / or prevention of asthma, chronic obstructive pulmonary disease, allergic rhinitis, nasal polyps, sinusitis, and perioperative recovery anti-inflammatory treatment of nasal polyps and sinusitis.

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