Methods of treating cataract surgical complications

Abstract

A method of treating or ameliorating cataract surgical complications is provided. The method comprises administering to a subject in need thereof a nanoparticle of beclosone propionate (CLOBETASOL PROPIONATE). The method comprises administering to the subject in need thereof a nanoparticle of beclosone propionate.

Description

Technical Field

[0001] The present invention relates to a method of treatment, and more particularly, to a method of treating complications of cataract surgery. Background Art

[0002] A cataract is a clouding of the lens in the eye that affects vision. Most people develop cataracts as a result of aging. Cataract surgery is one of the most common eye surgeries. The main goals of cataract surgery are to remove the cloudy lens, implant an artificial lens or intraocular lens (IOL), and restore some of the optical properties of the cloudy lens.

[0003] With new advances in technology, infectious disease control, and equipment, fewer adverse events occur after surgical procedures. However, complications still occur after surgery.

[0004] Therefore, there is a need for improved methods of treating complications of cataract surgery. SUMMARY OF THE INVENTION

[0005] The present invention provides a novel method for treating or improving complications of cataract surgery.

[0006] In one embodiment of the present invention, a method for treating or ameliorating cataract surgery complications in a subject in need thereof comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an aqueous suspension, wherein the aqueous suspension comprises: Nanoparticles of clobetasol propionate, wherein the average particle size of the nanoparticles is 300 nm or less and the D90 particle size of the nanoparticles is 450 nm or less; Physiologically acceptable salts; glycerin; Hydrogenated soy lecithin; and Anhydrous citric acid.

[0007] Examples of surgical complications include, but are not limited to, high anterior chamber cell (ACC) count, pain, impaired vision, eye inflammation, and eye infection.

[0008] In some embodiments of the present invention, the pharmaceutical composition is administered before, during, or after cataract surgery. In one embodiment of the present invention, the pharmaceutical composition is administered after cataract surgery.

[0009] In one embodiment of the present invention, the cataract surgery is non-complicated cataract surgery or complicated cataract surgery.

[0010] In some embodiments of the present invention, the aqueous suspension comprises 0.01 wt% to 0.2 wt%; 0.015 wt% to 0.18 wt%; 0.02 wt% to 0.16 wt%; 0.025 wt% to 0.14 wt%; 0.03 wt% to 0.12 wt%; 0.035 wt% to 0.1 wt%; 0.04 wt% to 0.08 wt%; 0.04 wt% to 0.06 wt%; 0.05 wt%; or 0.1 wt% of beclosonide.

[0011] In one embodiment of the present invention, the pharmaceutical composition is administered at least once.

[0012] In one embodiment of the present invention, the pharmaceutical composition is administered once, twice, three times or four times a day.

[0013] In one embodiment of the present invention, the pharmaceutical composition is administered on postoperative day 1 (POD 1).

[0014] In one embodiment of the present invention, the pharmaceutical composition is administered for at least one day. In one embodiment of the present invention, the pharmaceutical composition is administered for 3 to 28 days; 4 to 27 days; 5 to 26 days; 6 to 26 days; 7 to 25 days; 8 to 24 days; 9 to 23 days; 10 to 22 days; 11 to 21 days; 12 to 20 days; 13 to 19 days; 14 to 18 days; 15 to 17 days.

[0015] In some embodiments of the present invention, nanoparticles are produced by mixing beclosonide, a physiologically acceptable salt, glycerol, hydrogenated soy lecithin, and anhydrous citric acid.

[0016] In some embodiments of the present invention, nanoparticles are produced by further mixing beclosonide, a physiologically acceptable salt, glycerol, hydrogenated soy lecithin, and anhydrous citric acid with a surface modifier.

[0017] In some embodiments of the present invention, the surface modifier includes a surfactant, an aggregation inhibitor, a viscosity regulator, and / or a dispersion stabilizer.

[0018] In some embodiments of the present invention, the surface modifier is a dispersion stabilizer.

[0019] Examples of dispersion stabilizers include, but are not limited to, polyoxyethylene polyoxypropylene glycol and / or polyvinyl alcohol.

[0020] In some embodiments of the present invention, the surface modifier is a viscosity modifier.

[0021] Examples of viscosity modifiers include, but are not limited to, methylcellulose, hydroxypropylmethylcellulose, and polyvinyl alcohol.

[0022] In some embodiments of the present invention, the aqueous suspension comprises 1 to 10 mg / mL; 1.5 to 9.5 mg / mL; 2 to 9 mg / mL; 2.5 to 8.5 mg / mL; 3 to 8 mg / mL; 3.5 to 7.5 mg / mL; 4 to 7 mg / mL; 4.5 to 6.5 mg / mL; or 5 to 6 mg / mL of a viscosity modifier.

[0023] In some embodiments of the present invention, the pharmaceutical composition is administered in the form of eye drops.

[0024] The present invention provides an ophthalmic composition comprising: Nanoparticles of beclosonide propionate, wherein the average particle size of the nanoparticles is 300 nm or less and the D90 particle size of the nanoparticles is 450 nm or less; Physiologically acceptable salts; glycerin; hydrogenated soy lecithin; Anhydrous citric acid; Boric acid; Ethylene diamine tetraacetic acid (EDTA); and Benzalkonium chloride (BAK), The concentration of the benzalkonium chloride is lower than 45 ppm.

[0025] In some embodiments of the present invention, the ophthalmic composition comprises nanoparticles of beclosonide dipropionate, sodium chloride, hydrogenated soy lecithin, glycerin, anhydrous citric acid, polyvinyl alcohol, Poloxamer 407, BAK, methylcellulose, boric acid, and EDTA.

[0026] In some embodiments of the present invention, the ophthalmic composition comprises 0.05 wt% to 0.15 wt% of nanoparticles of beclosonide dipropionate, 0.5 wt% to 1.5 wt% of sodium chloride, 0.05 wt% to 0.15 wt% of hydrogenated soy lecithin, 0.1 wt% to 0.4 wt% of glycerol, 0.003 wt% to 0.01 wt% of anhydrous citric acid, 0.05 wt% to 0.15 wt% of polyvinyl alcohol, 0.002 wt% to 0.01 wt% of poloxamer 407, 0.003 wt% to 0.004 wt% of BAK, 0.3 wt% to 0.8 wt% of methylcellulose, 0.15 wt% to 0.35 wt% of boric acid, and 0.01 wt% to 0.07 wt% of EDTA.

[0027] These and other aspects will become apparent from the following description of the preferred embodiment when taken in conjunction with the following drawings, and changes and modifications may be made without departing from the spirit and scope of the novel concepts of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 Results are shown for mean anterior chamber cell counts following cataract surgery for treatment with Suspensions 1-2 and placebo Suspensions 1-2.

[0029] Figure 2 Shown are the percentages of subjects treated with Suspensions 1-2 and placebo Suspensions 1-2 at a given time point following cataract surgery with an ACC count of 0.

[0030] Figure 3 Shown are the percentages of subjects treated with Suspensions 1-2 and placebo Suspensions 1-2 following cataract surgery with a pain index of 0 at each time point. Detailed Description of the Invention

[0031] definition

[0032] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event of a conflict, the present document, including definitions, will control. As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the content clearly dictates otherwise.

[0033] Throughout this specification, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.

[0034] As used herein, the terms "treatment" and "treating" encompass both preventative (i.e., prophylactic) or therapeutic (i.e., curative and / or palliative) treatment. Thus, the terms "treatment" and "treating" encompass therapeutic treatment of a patient who has already developed the condition, especially in an overt form. Therapeutic treatment may be symptomatic treatment to alleviate the symptoms of a particular indication, or may be causal treatment to reverse or partially reverse the symptoms of the indication or to prevent or slow the progression of the disease. Thus, the conjugates, compositions and methods of the invention may be used, for example, as therapeutic treatments over a period of time as well as long-term therapies. Additionally, the terms "treatment" and "treating" encompass preventative treatment, i.e., treatment of a patient at risk of developing the conditions mentioned above, thereby reducing that risk.

[0035] As used herein, the term "therapeutically effective amount" means an amount of a conjugate of the invention that achieves the following goals: (i) treating or preventing a specific disease or condition, (ii) alleviating, ameliorating or eliminating one or more symptoms of a specific disease or condition, or (iii) preventing or delaying the onset of one or more symptoms of a specific disease or condition described herein.

[0036] As used interchangeably herein, the terms "individual," "subject," "subject," and "patient" refer to mammals, including but not limited to, murines (rats, mice), non-human primates, humans, canines, felines, ungulates (e.g., equines, bovines, ovines, porcines, goats), and the like.

[0037] As used herein, the term "in need of treatment" refers to a judgment made by a caregiver (e.g., a physician, nurse, care practitioner, or individual in the case of humans; a veterinarian in the case of animals (including non-human mammals)) that the subject requires or will benefit from treatment. This judgment is based on a variety of factors within the caregiver's area of ​​expertise, including knowledge that the subject is or will become ill with a condition that can be treated with the compounds of the invention.

[0038] Aqueous suspension containing beclorosone dipropionate nanoparticles

[0039] Specifically, the present inventors have discovered that when beclosonide nanoparticles have an average particle size of 300 nm or less and a 90% diameter (hereinafter referred to as "D90") of 450 nm or less (preferably, an average particle size of 250 nm or less and a D90 of 300 nm or less, or an average particle size of 200 nm or less and a D90 of 250 nm or less), the nanoparticles exhibit excellent ability to be transferred into aqueous humor and exhibit a favorable anti-inflammatory effect. When such nanoparticles are used, the solubility of beclosonide is expected to be higher, thereby increasing bioavailability and reducing the required dosage. The average particle size can be measured as a number distribution average particle size.

[0040] The average particle size range of the pulverized beclosonide propionate particles obtained by the above production method can be the same as the average particle size of the beclosonide propionate nanoparticles contained in the aqueous suspension or aqueous pharmaceutical composition described above. Furthermore, the 90% diameter (D90) and 50% diameter (D50) ranges of the pulverized beclosonide propionate particles obtained by the above production method can be the same as the 90% diameter (D90) and 50% diameter (D50) of the beclosonide propionate nanoparticles contained in the aqueous suspension or aqueous pharmaceutical composition described above, respectively.

[0041] The term "average particle size" herein refers to the arithmetic mean diameter of a particle size distribution measured by dynamic light scattering photon correlation spectroscopy. The 50% diameter (also known as the median diameter, D50) represents the diameter that separates the powder particles in the particle size distribution measured by the above measurement method into two groups, wherein the number of particles in the two groups, i.e., the larger diameter group and the smaller diameter group, is equal. The "90% diameter" refers to the diameter (D90) of particles at the 90th percentile position in the particle size distribution measured by the above measurement method, where the number of particles is counted from smaller to larger particle sizes, e.g., 0% (smallest) to 100% (largest particle). The "10% diameter" refers to the diameter (D10) of particles at the 10th percentile position in the particle size distribution measured by the above measurement method, where the number of particles is counted from smaller to larger particle sizes, e.g., 0% (smallest) to 100% (largest particle). The measurement method by dynamic light scattering photon correlation spectroscopy and the calculation method of particle size distribution are well known in the art.

[0042] Thus, in one embodiment, the present invention relates to an aqueous suspension containing nanoparticles of beclosonide, and preferably, the nanoparticles have an average particle size of 300 nm or less and a D90 of 450 nm or less. The aqueous suspension contains, for example, nanoparticles of beclosonide prepared by mixing beclosonide, a physiologically acceptable salt, a physiologically acceptable polyol, and / or water, and a surface modifier. Examples of surface modifiers include, but are not limited to, surfactants, aggregation inhibitors, viscosity modifiers, and dispersion stabilizers. More preferably, the aqueous suspension contains nanoparticles of beclosonide prepared by mixing beclosonide, a physiologically acceptable salt, glycerol, anhydrous citric acid, and hydrogenated soy lecithin.

[0043] The present inventors have also discovered that aqueous suspensions containing beclosonide nanoparticles, polyoxyethylene polyoxypropylene glycol (hereinafter referred to as "POE-POP diol") and / or polyvinyl alcohol (hereinafter referred to as "PVA") as dispersion stabilizers, and / or hydroxypropyl methylcellulose and / or methylcellulose as viscosity modifiers exhibit good long-term transparency, dispersibility, and storage stability.

[0044] Thus, in one embodiment, the present invention relates to an aqueous suspension containing nanoparticles of beclosonide having an average particle size of 300 nm or less and a D90 of 450 nm or less (preferably, an average particle size of 250 nm or less and a D90 of 300 nm or less, or an average particle size of 200 nm or less and a D90 of 250 nm or less). In another embodiment, the present invention relates to an aqueous pharmaceutical composition containing nanoparticles of beclosonide as an active pharmaceutical agent and a dispersion stabilizer and / or viscosity modifier as an additive.

[0045] As used herein, an "aqueous pharmaceutical composition" refers to an aqueous liquid or gel pharmaceutical composition, specifically a pharmaceutical composition containing nanoparticles of beclosonide suspended in an aqueous liquid or gel. Therefore, unless otherwise specified, pharmaceutical compositions herein refer to aqueous pharmaceutical compositions. Aqueous pharmaceutical compositions include topical formulations. Therefore, topical formulations herein refer to aqueous formulations for topical administration. Aqueous pharmaceutical compositions may be viscous, as long as this does not prevent the composition from being used as a pharmaceutical, and include gel formulations as well as aqueous formulations.

[0046] The term "local area" as used herein means a part of the body including the affected part, the area around the affected part or the organ including the affected part, and preferably the eye.

[0047] As used herein, "topical preparations" refer to pharmaceutical compositions for topical application. Topical preparations preferably include topical eye preparations (eg, eye drops).

[0048] The aqueous pharmaceutical composition can be used to treat or prevent cataract surgery complications by topically administering an effective amount thereof to a patient in need thereof. In other words, in one embodiment, the present invention relates to a method for treating or preventing inflammatory or infectious diseases, comprising administering to a patient in need thereof a therapeutically effective amount of an aqueous suspension or a pharmaceutical composition comprising an aqueous suspension, wherein the aqueous suspension or pharmaceutical composition comprises nanoparticles of beclosonide and, optionally, a dispersion stabilizer and / or viscosity modifier.

[0049] Alternatively, the present invention relates to the use of nanoparticles of beclosonide (optionally together with a surface modifier, a surfactant, an aggregation inhibitor, a dispersion stabilizer and / or a viscosity regulator) or an aqueous suspension containing the nanoparticles for the manufacture of aqueous pharmaceutical compositions (e.g., injections and topical preparations).

[0050] The term "aqueous suspension" herein refers to an aqueous liquid in which the nanoparticles of beclosonide dipropionate are suspended. The aqueous suspension herein may constitute a pharmaceutical composition, which may be administered as a drug itself, or may be constituted by adding other components and diluents (e.g., raw materials for pharmaceutical compositions), or may not be used as a drug.

[0051] The aqueous suspension herein includes a stable dispersion aqueous suspension. Stable dispersion means that the aqueous suspension has any one or two or more of the following characteristics: (1) no precipitation is confirmed under visual inspection, (2) high transparency; (3) no agglomerates or crystals are observed under microscopic observation, and (4) at room temperature (25°C), after dispersion is achieved by stirring and then allowed to stand for 24 hours (preferably 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year or 2 years), the average particle size value does not change substantially (not more than 50%). The aqueous suspension containing nanoparticles of beclosonide herein is preferably an aqueous suspension that is confirmed to have no precipitation under visual inspection after being sealed in a test tube for 7 days, has high transparency, and no agglomerates or crystals are observed under microscopic observation.

[0052] Transparency can be measured according to the transparency test described in the Japanese Pharmacopoeia. Specifically, transparency can be measured according to the following procedure. Water is added to 5 mL of formazine standard until 100 mL is reached, which is used as a turbidity standard. Each of the tested aqueous suspension and the newly prepared turbidity standard is transferred to a colorless, transparent glass flat-bottomed test tube with an inner diameter of 15 mm so that the liquid layer has a depth of 30 mm or 40 mm, and then compared with other liquid layers by observing from above on a black background in scattered light. When the transparency of the tested aqueous suspension is the same as water or the solvent used, or when the turbidity of the tested aqueous suspension is lower than the turbidity standard, transparency is measured as high. Alternatively, the transmittance of the tested aqueous suspension and a freshly prepared turbidity standard is measured at 660 nm by UV-visible spectrophotometry using a 50 mm layer cell with water or solvent as a control. The transparency of the tested aqueous suspension is determined to be high when the transmittance of the tested aqueous suspension is higher than that of the turbidity standard.

[0053] In another embodiment, the topical formulation is a topical ophthalmic formulation capable of transferring into aqueous humor. "Capable of transferring into aqueous humor" herein may mean that 60 minutes after application of a single eye drop containing an aqueous topical formulation adjusted to 0.05% (w / v) beclosone dipropionate, the concentration (average) of beclosone dipropionate in the aqueous humor is 45 ng / mL or more (preferably 50 ng / mL or more, 55 ng / mL or more, 60 ng / mL or more, 65 ng / mL or more, 70 ng / mL or more, 75 ng / mL or more). Alternatively, "ability to transfer into aqueous humor" may mean that 30 minutes after application of a single eye drop containing an aqueous topical formulation of beclosonide adjusted to 0.05% (w / v), the concentration (average) of beclosonide in the aqueous humor is 40 ng / mL or greater (preferably 50 ng / mL or greater, 55 ng / mL or greater, 60 ng / mL or greater, 63 ng / mL or greater, 64 ng / mL or greater, 65 ng / mL or greater, 70 ng / mL or greater, 75 ng / mL or greater).

[0054] In another embodiment, the topical formulation is a topical ocular formulation capable of transferring to the conjunctiva. "Capable of transferring to the conjunctiva" herein means that 15 minutes after application of a single eye drop of an aqueous topical formulation containing beclosone dipropionate adjusted to 0.05% (w / v), the concentration (average) of beclosone dipropionate in the conjunctiva is 500 ng / mL or more (preferably 659 ng / mL or more, 900 ng / mL or more, 972 ng / mL or more, 1000 ng / mL or more, 1200 ng / mL or more, 1210 ng / mL or more, 1400 ng / mL or more, 1455 ng / mL or more, 1500 ng / mL or more, or 2000 ng / mL or more, 2141 ng / mL or more).

[0055] The ability to transfer to the aqueous humor and conjunctiva can be determined using suitable animals according to the methods described in the examples of this application, for example, by the following procedure. The lower eyelid of the rabbit is gently pulled open, and the eye drops of the test substance are administered (single eye drop application) into the conjunctival sac of the left eye using a pipette. After application, the upper and lower eyelids are gently closed and held for approximately 2 seconds. 15 minutes, 30 minutes, 60 minutes, and 90 minutes after application, the rabbits are anesthetized and sacrificed by exsanguination, followed by thorough washing of the eyes with water for injection, and the aqueous humor and conjunctiva are collected. The concentration of beclosone propionate in the collected aqueous humor can be determined by adding methanol and an internal standard (prednisolone) solution to the collected aqueous humor, stirring the mixture, then adding acetonitrile thereto, stirring the mixture, and centrifuging the mixture (13,100×g, 4°C, 5 minutes), followed by measuring the supernatant obtained by the centrifuge by LC-MS / MS. The concentration of beclosone propionate in the collected conjunctiva can be determined by adding ultrapure water in a volume nine times the wet weight of the collected conjunctiva, homogenizing, further adding methanol and an internal standard (prednisolone) solution thereto, stirring the mixture, then adding acetonitrile thereto, stirring the mixture, and centrifuging the mixture (13,100×g, 4°C, 5 minutes), followed by measuring the supernatant obtained by the centrifuge by LC-MS / MS.

[0056] In another embodiment, the topical formulation is a topical ocular formulation capable of reducing the rate of increase in protein concentration in aqueous humor. "Capable of reducing the rate of increase in protein concentration in aqueous humor" means that the protein concentration in aqueous humor obtained is less than three times (preferably less than 2.5 times or less than two times) the protein concentration in aqueous humor of an eye that has not undergone corneal puncture by administering 40 μL of an aqueous topical formulation containing 0.05% (w / v) or 0.1% (w / v) beclosone propionate to an experimental animal (e.g., a rabbit) seven times at intervals of 30 to 60 minutes before and after corneal puncture (preferably, the time of corneal puncture is set to 0 minutes, and the seven administrations are performed 180 minutes, 120 minutes, 60 minutes, and 30 minutes before corneal puncture, and 30 minutes, 60 minutes, and 90 minutes after corneal puncture), and collecting aqueous humor 30 minutes after the last administration.

[0057] Topical ophthalmic formulations may have two or more (two, three or all) properties selected from the group consisting of the ability to transfer into the aqueous humor, the ability to transfer into the conjunctiva, reducing the rate of increase of protein concentration in the aqueous humor, and anti-inflammatory activity in the eye.

[0058] In one embodiment, the aqueous suspension is an aqueous suspension with low irritation. Low irritation herein means that the degree of irritation (inflammatory reaction, such as redness, swelling and / or congestion) when the aqueous suspension is administered to a subject is lower than the degree of irritation when a previously used aqueous formulation containing the same active ingredient is administered. Whether the aqueous suspension is low in irritation can be determined, for example, by referring to the method of Jonas, J. Kuehne et al., Am J Ophthalmol (2004) 138: 547-553: by administering a test aqueous suspension to a rabbit's eye, measuring the degree of eye inflammation, and determining that the irritation is low when the degree of inflammation is lower than that of a standard liquid preparation (same as described above). More specifically, in the case of eye drops, irritation is determined by applying a preparation containing 1.0% beclosonide propionate to the eyes once to 20 times a day at intervals of 30 minutes to several hours, observing the cornea, iris, and conjunctiva before application and 1, 3, 5, and 24 hours after the last application, and scoring according to Draize's scoring criteria (see OECD GUIDELINES FOR TESTING OF CHEMICALS 405 (February 24, 1987) Acute Eye Irritation / Corrosion).

[0059] The aqueous suspension or pharmaceutical composition may contain one or two or more physiologically acceptable salts. Examples of "physiologically acceptable salts" include sodium chloride, potassium chloride, ammonium chloride, sodium sulfate, magnesium sulfate, potassium sulfate, calcium sulfate, sodium malate, sodium citrate, disodium citrate, sodium dihydrogen citrate, potassium dihydrogen citrate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, and dipotassium hydrogen phosphate, with sodium chloride being preferred.

[0060] The aqueous suspension or pharmaceutical composition may contain a physiologically acceptable salt at a concentration of 0.01 to 10%, preferably 0.1 to 5%, or for example 0.5 to 3% and 0.8 to 2%. Alternatively, the aqueous suspension or pharmaceutical composition may contain a physiologically acceptable salt at a concentration of 0.01 to 50 mg / mL, 0.1 to 20 mg / mL, or 1 to 5 mg / mL.

[0061] The aqueous suspension or pharmaceutical composition may contain one or two or more surfactants and / or one or two or more aggregation inhibitors.

[0062] The "surfactant" is not limited as long as it can be administered to humans as a pharmaceutical additive without showing toxicity and without interfering with the activity of beclosone propionate. The surfactant may be, for example, a nonionic surfactant, including polyoxyethylene (hereinafter referred to as "POE")-polyoxypropylene (hereinafter referred to as "POP") block copolymers, such as poloxamer 407, poloxamer 235 and poloxamer 188; adducts of ethylenediamine and polyoxyethylene-polyoxypropylene block copolymers, such as poloxamine; POE sorbitan fatty acid esters, such as POE (20) sorbitan monolaurate (polysorbate 20), POE (20) sorbitan monooleate (polysorbate 80) and polysorbate 60; POE hydrogenated castor oil, such as POE (60) hydrogenated castor oil; POE alkyl ethers, such as P OE(9) lauryl ether; POE-POP alkyl ethers, such as POE(20)POP(4) hexadecyl ether; POE alkylphenyl ethers, such as POE(10) nonylphenyl ether; POE-POP diols, such as POE(105)POP(5) diol, POE(120)POP(40) diol, POE(160)POP(30) diol, POE(20)POP(20) diol, POE(200)POP(70) diol, POE(3)POP(17) diol alcohol, POE(42)POP(67)diol, POE(54)POP(39)diol and POE(196)POP(67)diol; amphoteric surfactants, including glycine type surfactants (such as alkyldiaminoethylglycine), acetate betaine type surfactants (such as lauryldimethylaminoacetic acid betaine) and imidazoline type surfactants; anionic surfactants, including POE alkyl ether phosphate and its salts (such as POE(10) sodium lauryl ether phosphate), N-acylamino acid salts (such as sodium lauroyl methylalanine), alkyl ether carboxylates, N-acyl taurates (such as sodium cocoyl N-methyl taurate), sulfonates (such as sodium tetradecene sulfonate), alkyl sulfates (such as sodium lauryl sulfate), POE alkyl ether sulfates (such as sodium POE (3) lauryl ether sulfate) and α-olefin sulfonates; and cationic surfactants including alkylamine salts, alkyl quaternary ammonium salts (benzalkonium chloride and benzethonium chloride) and alkyl pyridinium salts (cetylpyridinium chloride and cetylpyridinium bromide). The aqueous suspension may contain one or two or more surfactants.

[0063] The "aggregation inhibitor" herein is not limited as long as it inhibits the aggregation of beclosone propionate and can be administered to humans without showing toxicity and without interfering with the activity of beclosone propionate. The aggregation inhibitor may be phospholipids (such as alkyl sulfate, N-alkanoylmethyl taurate, ethanol, glycerol, propylene glycol, sodium citrate) (phospholipids include glycerophospholipids (lecithin (phosphatidylcholine) (e.g., refined soybean lecithin, hydrogenated soybean lecithin), phosphatidylserine, phosphatidylethanolamine, phosphatidic acid inositol, phosphatidic acid, phosphatidylglycerol, lysophosphatidylcholine, lysophosphatidylserine, lysophosphatidylethanolamine, lysophosphatidylinositol, lysophosphatidic acid and lysophosphatidylglycerol) and sphingomyelin (sphingomyelin, ceramide, sphingosine or ganglioside)), D-sorbitol, lactose, xylitol, gum arabic (gum Arabic), sucrose fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene fatty acid esters, polyethylene glycol (PEG), polyoxyethylene sorbitan fatty acid esters, alkylbenzene sulfonates, sulfosuccinates, POE-POP diol, polyvinyl pyrrolidone, PVA, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, carboxyvinyl polymer, N-acyl-glutamic acid, acrylic acid copolymer, methacrylic acid copolymer, sodium caseinate, L-valine, L-leucine, L-isoleucine, benzalkonium chloride and benzethonium chloride. The aqueous suspension may contain one agglomeration inhibitor or two or more agglomeration inhibitors.

[0064] The aqueous suspension or pharmaceutical composition may contain an aggregation inhibitor at a concentration of 0.001 to 10%, or 0.01 to 10%, preferably 0.02 to 5%, such as 0.03 to 1%, 0.04 to 0.5%, or 0.05 to 0.2%. Alternatively, the aqueous suspension or pharmaceutical composition may contain an aggregation inhibitor at a concentration of 0.01 to 50 mg / mL, 0.1 to 20 mg / mL, or 1 to 5 mg / mL.

[0065] The surfactant and / or agglomeration inhibitor is preferably one or more substances selected from the following: polyoxyethylene hydrogenated castor oil 60 (e.g., HCO-60), polyoxyethylene hydrogenated castor oil 40 (e.g., HCO-40), polysorbate 80 (e.g., Tween 80), polysorbate 20 (e.g., Tween 20), POE-POP diol (e.g., PLONON 407P, Pluronic F68, UNILUBE 70DP-950B), and PVA (e.g., Kuraray POVAL 217C), and more preferably one or more substances selected from POE-POP diol and PVA.

[0066] The "viscosity regulator" herein is not limited, as long as it can regulate the viscosity of the aqueous suspension and can be administered to humans as a pharmaceutical additive without showing toxicity and without interfering with the activity of becloral propionate. The viscosity regulator can be a polysaccharide or a derivative thereof (gum arabic, gum karaya, xanthan gum, carob gum, guar gum, guaiac gum, quince seed, darman gum, tragacanth gum, benzoin rubber, locust bean gum, casein, agar, alginic acid, The aqueous suspension may contain one or more viscosity modifiers. The viscosity modifier is preferably one or more substances selected from the following: hydroxypropyl methylcellulose (e.g., TC-5(R), Metlose 60SH-50), PVA (Kurary POVAL 217C), and methylcellulose (e.g., Metlose SM-100, Metlose SM-15), and more preferably one or more substances selected from hydroxypropyl methylcellulose and methylcellulose.

[0067] The aqueous suspension may contain 1 to 10 mg / mL, preferably 1 to 5 mg / mL, for example 1 to 4 mg / mL, 1 to 3 mg / mL, or 1 to 2 mg / mL of the viscosity regulator.

[0068] The "surface modifier" herein refers to a surfactant, an aggregation inhibitor, a viscosity regulator and / or a dispersion stabilizer, and the surface modifier is capable of modifying the surface of the beclosonide nanoparticles.

[0069] The “dispersion stabilizer” that can be used herein is listed above as a surfactant, agglomeration inhibitor and / or viscosity modifier, and is preferably one or more substances selected from polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 40, polysorbate 80, polysorbate 20, POE-POP diol, PVA, hydroxypropyl methylcellulose and methylcellulose, and more preferably one or more substances selected from POE-POP diol, PVA, hydroxypropyl methylcellulose and methylcellulose.

[0070] Surfactants, aggregation inhibitors, and / or viscosity modifiers (hereinafter referred to as "additives" in this paragraph) that also function as dispersion stabilizers may adhere to or be adsorbed on the surface of the beclosonide propionate nanoparticles. When these additives are added prior to the pulverization step, they adhere to or are adsorbed on the surface of the beclosonide propionate nanoparticles, which inhibits nanoparticle aggregation during the pulverization step. By adhering to or adsorbing on the surface of the beclosonide propionate nanoparticles, the additives effectively inhibit aggregation in the aqueous suspension. In this context, as long as at least a portion of the additives adhere to or are adsorbed on the surface of the nanoparticles (promoting surface modification), it is considered that the surfactants, aggregation inhibitors, and / or viscosity modifiers that also function as dispersion stabilizers adhere to or are adsorbed on the surface of the beclosonide propionate nanoparticles, and the additives do not necessarily adhere to or be adsorbed in the aqueous suspension.

[0071] The aqueous suspension or pharmaceutical composition may contain one or two or more physiologically acceptable polyols. The pharmaceutical composition may contain, for example, the physiologically acceptable polyols described above. "Physiologically acceptable polyols" include glycerol, propylene glycol, polyethylene glycol, dipropylene glycol, and ethylene glycol, and preferably propylene glycol or glycerol. The aqueous suspension or pharmaceutical composition may contain a concentration of, for example, 0.001 to 10% or 0.01 to 10%, preferably 0.02 to 5%, such as 0.03 to 1%, 0.04 to 0.5%, 0.05 to 0.2% of the physiologically acceptable polyol. Alternatively, the aqueous suspension or pharmaceutical composition may contain a concentration of 0.01 to 10 mg / mL, 0.05 to 5 mg / mL, or 0.1 to 3 mg / mL of the physiologically acceptable polyol.

[0072] Aqueous suspensions or aqueous pharmaceutical compositions do not contain oily solvents. Oily solvents refer to solvents that are insoluble or slightly soluble in water.

[0073] The beclosonide dipropionate contained in the aqueous suspension or aqueous pharmaceutical composition is in the form of nanoparticles. The average particle size of the beclosonide dipropionate nanoparticles may be 300 nm or less, preferably 250 nm or less, 240 nm or less, 230 nm or less, 220 nm or less, 210 nm or less, 200 nm or less, 190 nm or less, 180 nm or less, 170 nm or less, 160 nm or less, 150 nm or less, 140 nm or less, 130 nm or less, 120 nm or less, or 110 nm or less. The average particle size of beclosonide propionate can range from, for example, 50 to 300 nm, 50 to 250 nm, 50 to 240 nm, 50 to 230 nm, 50 to 220 nm, 50 to 210 nm, 50 to 200 nm, 50 to 190 nm, 50 to 180 nm, 50 to 170 nm, 50 to 160 nm, 50 to 150 nm, 50 to 140 nm, 50 to 130 nm, 50 to 120 nm, 50 to 110 nm , 100 to 300 nm, 100 to 250 nm, 100 to 240 nm, 100 to 230 nm, 100 to 220 nm, 100 to 210 nm, 100 to 200 nm, 100 to 190 nm, 100 to 180 nm, 100 to 170 nm, 100 to 160 nm, 100 to 150 nm, 100 to 140 nm, 100 to 130 nm, 100 to 120 nm or 100 to 110 nm.

[0074] The 90% diameter (D90) of the beclosonide nanoparticles contained in the aqueous suspension or aqueous pharmaceutical composition is 450 nm or less, preferably 400 nm or less, 350 nm or less, 300 nm or less, 290 nm or less, 280 nm or less, 270 nm or less, 260 nm or less, 250 nm or less, 240 nm or less, or 230 nm or less. The 90% diameter (D90) of beclosonide propionate can range from, for example, 50 to 400 nm, 50 to 350 nm, 50 to 300 nm, 50 to 290 nm, 50 to 280 nm, 50 to 270 nm, 50 to 260 nm, 50 to 250 nm, 50 to 240 nm, 50 to 230 nm, 100 to 400 nm, 100 to 350 nm, 100 to 300 nm, 100 to 290 nm, 100 to 280 nm, 100 to 270 nm, 100 to 260 nm, 100 to 250 nm, 100 to 240 nm, or 100 to 230 nm.

[0075] The 50% diameter (D50) of the beclosonide nanoparticles contained in the aqueous suspension or aqueous pharmaceutical composition may be 200 nm or less, preferably 190 nm or less, 180 nm or less, 170 nm or less, 160 nm or less, 150 nm or less, 140 nm or less, 130 nm or less, 120 nm or less, 110 nm or less, or 100 nm or less. The 50% diameter (D50) of beclosonide propionate may range from 50 to 190 nm, 50 to 180 nm, 50 to 170 nm, 50 to 160 nm, 50 to 150 nm, 50 to 140 nm, 50 to 130 nm, 50 to 120 nm, 50 to 110 nm, 50 to 100 nm, 80 to 190 nm, 80 to 180 nm, 80 to 170 nm, 80 to 160 nm, 80 to 150 nm, 80 to 140 nm, 80 to 130 nm, 80 to 120 nm, 80 to 110 nm, or 80 to 100 nm.

[0076] The beclosonide nanoparticles contained in the aqueous suspension or aqueous pharmaceutical composition may meet two or more particle size conditions selected from the average particle size, 90% diameter (D90), and 50% diameter (D50) described above. The beclosonide nanoparticles contained in the aqueous suspension may have, for example, an average particle size of 166 nm or less, a D50 of 138 nm or less, and / or a D90 of 241 nm or less. The beclosonide nanoparticles contained in the aqueous pharmaceutical composition may have, for example, an average particle size of 204 nm or less, a D50 of 177 nm or less, and / or a D90 of 306 nm or less.

[0077] Beclosonide as the active ingredient contained in the aqueous suspension is in the form of nanoparticles, which enables the aqueous suspension to be filter sterilized, and thus the aqueous suspension can be easily sterilized with minimal effect on the physicochemical properties of the active ingredient.

[0078] The nanoparticles of beclosonide propionate contained in the aqueous suspension are preferably prepared by mixing beclosonide propionate, a physiologically acceptable salt, a physiologically acceptable polyol, and a dispersion stabilizer. More preferably, the nanoparticles of beclosonide propionate are prepared by mixing beclosonide propionate, a physiologically acceptable salt, a physiologically acceptable polyol, and a dispersion stabilizer and adding lecithin (e.g., hydrogenated soy lecithin) during or after pulverization.

[0079] Aqueous suspensions include, for example, formulations containing: nanoparticles of beclosonide; sodium chloride; hydrogenated soy lecithin; glycerol; anhydrous citric acid; one or more substances selected from POE-POP diol, polyoxyethylene hydrogenated castor oil, polysorbate 80, PVA, and POE-POP block copolymers; benzalkonium chloride, sorbic acid or its salts (potassium sorbate, sodium sorbate, and triclocarban sorbate) or paraoxybenzoates (methylparaben, ethylparaben, propylparaben, and butylparaben); hydroxypropyl methylcellulose and / or methylcellulose; and sodium citrate (including trisodium citrate).

[0080] Aqueous suspensions and pharmaceutical compositions may contain water as a major component. The pharmaceutical compositions, aqueous suspensions and / or diluents herein may contain various additives, such as stabilizers, flavorings, thickeners, surfactants, preservatives, disinfectants or antibacterial agents, pH control agents, tonicity agents, and buffers as needed.

[0081] Preservatives and disinfectants or antimicrobial agents include sorbic acid or its salts (potassium sorbate, sodium sorbate and triclocarban sorbate), parabens (methyl paraben, ethyl paraben, propyl paraben and butyl paraben), acrinol, methylrosanilinium chloride, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetylpyridinium bromide, chlorhexidine or its salts, polyhexamethylene biguanide, alkylpolyaminoethylglycine, benzyl alcohol, phenylethyl alcohol, chlorobutanol, isopropyl alcohol, ethanol, phenoxyethanol, silver zirconium phosphate, mercurochrome red, povidone iodine, iodine), thimerosal, dehydroacetic acid, chloroxylenol, chlorophenol, resorcinol, o-phenylphenol, isopropylmethylphenol, thymol, hinokitiol, sulfonamides, lysozyme, lactoferrin, triclosan, 8-hydroxyquinoline, undecylenic acid, octanoic acid, propionic acid, benzoic acid, halocarban, thiabendazole, polymyxin B, 5-chloro-2-methyl-4-isothiazolin-3-one, 2-methyl-4-isothiazolin-3-one, polylysine, hydrogen peroxide, polidronium chloride Examples of the present invention include polydiaryldimethylammonium chloride, Glokill (trade name: for example, Glokill PQ from Rhodia), polydiaryldimethylammonium chloride, poly[ethyleneoxydichloride (dimethylimino)ethylene-(dimethylimino)ethylene], polyethylene polyamine-dimethylamine epichlorohydrin polycondensate (trade name: for example, Busan 1157 from Buckman Laboratories International, Inc.), and biguanide compounds (Cosmocil CQ (trade name, polyhexamethylene biguanide hydrochloride containing about 20 wt %, Arch Personal Care Products LP)), and pharmacologically acceptable salts thereof. Benzalkonium chloride is preferred.

[0082] pH control agents include inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid and boric acid), organic acids (lactic acid, acetic acid, citric acid, anhydrous citric acid, tartaric acid, malic acid, succinic acid, oxalic acid, gluconic acid, fumaric acid, propionic acid, aspartic acid, ε-aminocaproic acid, glutamic acid and aminoethylsulfonic acid), gluconolactone, ammonium acetate, inorganic bases (sodium bicarbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide and magnesium hydroxide), organic bases (monoethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine and lysine), borax and pharmacologically acceptable salts thereof.

[0083] Tonicity agents include inorganic salts (sodium chloride, potassium chloride, sodium carbonate, sodium bicarbonate, calcium chloride, magnesium sulfate, sodium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium thiosulfate, and sodium acetate), polyols (glycerol, propylene glycol, ethylene glycol, and 1,3-butylene glycol), and carbohydrates (glucose, mannitol, and sorbitol).

[0084] Buffers include Tris buffer, borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, ε-aminocaproic acid, and aspartic acid. Specific examples include boric acid or its salts (sodium borate, potassium tetraborate, and potassium metaborate), phosphoric acid or its salts (sodium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate), carbonic acid or its salts (sodium bicarbonate and sodium carbonate), and citric acid or its salts (sodium citrate, potassium citrate, and anhydrous citric acid).

[0085] "Thickening agents" refer to substances that increase the viscosity and / or physical stability of the pharmaceutical compositions of the present invention. Suitable thickening agents for the purposes of the present invention include, but are not limited to, stearyl alcohol, carbopol, dimethicone, and polymers.

[0086] The viscosity of the aqueous suspension and pharmaceutical composition herein may be 1 to 5 mPa·s, and may be, for example, 1 to 3 mPa·s.

[0087] Unless otherwise indicated, "%" or amounts as used herein in compositions refer to wt% (w / w).

[0088] The aqueous suspension of beclosonide nanoparticles of the present invention has advantages in terms of transparency, dispersibility, storage stability, transferability to the conjunctiva and transferability to the aqueous humor, as well as low irritation. It is therefore easy to sterilize and has good temporal and dispersion stability. The suspension can be used for parenteral administration, specifically as a pharmaceutical composition for eye drops.

[0089] Beclosonide propionate nanoparticles can be prepared by mixing beclosonide with a physiologically acceptable salt and a physiologically acceptable polyol, and wet-milling the organic compound. The production method is described in detail in International Publication No. WO2008 / 126797. The mixing step only requires that the beclosonide, physiologically acceptable salt, and physiologically acceptable polyol are ultimately mixed together, and the order of addition is not limited. The mixing step can be achieved, for example, by adding the physiologically acceptable salt and physiologically acceptable polyol to beclosonide, or by adding beclosonide to the physiologically acceptable salt and physiologically acceptable polyol. The beclosonide nanoparticles contained in the powder of the present invention can be prepared by adding the physiologically acceptable salt and physiologically acceptable polyol to an organic compound with a melting point of 80°C or higher, and wet-milling the organic compound. In this method, an aqueous suspension can be prepared without removing the salt and polyol. Because there is no need to remove salts and polyols, the suspension can be prepared in a very simple process. Wet pulverization is achieved by mixing the organic compound, salt, and polyol and kneading the mixture. Beclosone propionate nanoparticles can be prepared preferably by adding lecithin during or after the pulverization step.

[0090] Preferably, the beclosonide propionate nanoparticles are prepared by wet pulverization without using a hard solid pulverization aid, more preferably without using a solid pulverization aid such as glass products, metal products (such as stainless steel), ceramic products (such as zirconium oxide and aluminum oxide), and macromolecular products (such as rigid polystyrene). Most preferably, the beclosonide propionate nanoparticles are prepared by wet pulverization without using a solid pulverization aid other than a physiologically acceptable salt and a viscosity modifier.

[0091] The term "physiologically acceptable" means that a substance is not expected to cause physiological problems when administered to the body. The physiological acceptability of a substance is determined appropriately based on the substance being administered and the mode of administration. Examples of physiologically acceptable solvents include substances approved as additives or solvents for use in drugs or foods.

[0092] The "physiologically acceptable salt" herein is not limited as long as it can be administered without causing physiological problems. Physiologically acceptable salts preferably have lower solubility in polyols, higher solubility in water and / or low hygroscopicity, and have a hardness suitable for crushing organic compounds. More preferably, the physiologically acceptable salt used in the method for preparing becloronal propionate nanoparticles has two or more of these characteristics. The solubility of the physiologically acceptable salt in polyols is preferably 10% (mass / volume) or less. Physiologically acceptable salts are preferably highly soluble in water to facilitate removal after crushing. Specific examples include the salts listed above in this specification.

[0093] The "physiologically acceptable salt" is preferably pulverized before mixing with beclosone dipropionate to adjust the particle size. Furthermore, the physiologically acceptable salt may be dried at a temperature of 30 to 200°C under reduced pressure to reduce the water content, thereby preventing particle fusion and growth caused by the water content. When the particle size of the physiologically acceptable salt is pre-adjusted, the particle volume average diameter may be, for example, 5 to 300 μm, 10 to 200 μm, preferably 0.01 to 300 μm, more preferably 0.1 to 100 μm, even more preferably 0.5 to 50 μm, and most preferably 1 to 5 μm. The amount of salt used is preferably 1 to 100 times the mass of beclosone dipropionate, more preferably 5 to 30 times, and even more preferably 10 to 20 times. Only one salt may be used, or two or more salts may be used together.

[0094] The "physiologically acceptable polyol" used in the method for preparing beclosonide nanoparticles is not limited, as long as it can be used without causing any physiological problems. Preferred physiologically acceptable polyols have low solubility in salts, high solubility in water, a low freezing point, and / or a high flash point. Physiologically acceptable polyols are preferably highly soluble in water to facilitate removal after pulverization.

[0095] The polyol used in the method for preparing beclorosolone propionate nanoparticles preferably has a high viscosity. The viscosity of the polyol at 20°C may be 40 mPa·s or higher, preferably 50 mPa·s or higher, and more preferably 80 mPa·s or higher. The upper limit of the viscosity of the polyol used in the method for preparing beclorosolone propionate nanoparticles at 20°C is not limited and can be selected, for example, from a range of 40 mPa·s or higher to 5,000 mPa·s or lower, preferably 50 mPa·s or higher to 3,000 mPa·s or lower, and more preferably 80 mPa·s or higher to 2,000 mPa·s or lower. Specific examples include the polyols listed above in this specification.

[0096] The amount of the physiologically acceptable polyol used in the method for preparing beclosonide nanoparticles is preferably 0.5 to 100 times, more preferably 1 to 10 times, the mass of the organic compound to be pulverized. The type of polyol can be appropriately determined based on the solubility of the organic compound to be pulverized. A single polyol may be used, or two or more polyols may be used in combination.

[0097] In the method for producing nanoparticles of beclosonide propionate, the kneaded product containing beclosonide propionate, a polyol, and a salt preferably has a high viscosity. The viscosity of the kneaded product can be preferably increased by using a mixture of a viscosity modifier added to the polyol, or by adding a viscosity modifier that effectively improves pulverization efficiency separately from the polyol. The viscosity modifier described above can be added to the polyol. The viscosity of the polyol to which the viscosity modifier is added at 20°C is preferably 1,000 mPa·s or higher, more preferably 2,000 mPa·s or higher, even more preferably 5,000 mPa·s or higher, and most preferably 10,000 mPa·s or higher. The upper limit of the viscosity of the polyol to which the viscosity modifier is added at 20° C. is not limited and can be selected, for example, from a range of 1,000 mPa·s or more to 5,000,000 mPa·s or less, preferably 1,000 mPa·s or more to 1,000,000 mPa·s or less, more preferably 2,000 mPa·s or more to 500,000 mPa·s or less, more preferably 5,000 mPa·s or more to 300,000 mPa·s or less, and most preferably 10,000 mPa·s or more to 100,000 mPa·s or less.

[0098] In the method for preparing beclosonide propionate nanoparticles, any mill can be used for wet pulverization of beclosonide propionate without limitation, as long as it can mechanically knead and disperse beclosonide propionate, salt, polyol, and / or dispersion stabilizer. Examples of commonly used mills include kneaders, two-rollers, three-rollers, twin-shaft mills, Hoover mills, and disk blade kneader dispersers.

[0099] The pulverization temperature can be appropriately determined depending on the beclorosone propionate to be pulverized and the type of grinder. The pulverization temperature is not limited, but is preferably -50 to 50°C, more preferably -20 to 30°C, and most preferably -10 to 25°C. The pulverization time can also be appropriately determined depending on the organic compound to be pulverized and the type of grinder. The pulverization time can be, for example, 1 to 50 hours, 2 to 30 hours, 3 to 20 hours, 4 to 18 hours, and 5 to 10 hours.

[0100] After the beclosonide propionate is pulverized, the target pulverized beclosonide propionate particles can be obtained without removing the salt and polyol used for pulverization. Because a washing step is unnecessary, nanoparticle preparations can be prepared more simply and at a lower cost. A suspension can be prepared by homogenizing a mixture of beclosonide propionate, salt, polyol, and / or viscosity modifier in a solvent using a homogenizer. The solvent used to homogenize the mixture is not limited, as long as it easily dissolves the polyol, salt, and viscosity modifier while minimally dissolving the pulverized beclosonide propionate and is physiologically acceptable. The solvent is preferably water, but any solvent other than water can be used, including mixtures of water and organic solvents (such as acetic acid, methanol, or ethanol). The homogenized mixture can be filtered, if desired. The filtration method is not limited; any known filtration method for filtering organic compounds contained therein can be used. Examples of filtration methods include vacuum filtration, pressure filtration, and ultrafiltration membrane filtration.

[0101] Crushed particles generally have high surface energy and are therefore prone to agglomeration. Therefore, an agglomeration inhibitor as described above may be added after removing salts, etc., to prevent secondary agglomeration. Only one agglomeration inhibitor may be used, or two or more agglomeration inhibitors may be used together.

[0102] After removing the salt and polyol, the resulting pulverized beclorosone propionate particles can be dried to remove the solvent used to remove the salt, etc. The drying method is not limited; any method commonly used for drying organic compounds can be used. Examples of drying methods include reduced pressure drying, freeze drying, spray drying, and spray freeze drying. The drying temperature and drying time in these drying methods are not limited, but low temperatures are preferred for maintaining the chemical stability of the organic compound particles for medical use and preventing secondary particle agglomeration. For the same reason, freeze drying, spray drying, and spray freeze drying are preferred.

[0103] Pharmaceutical composition

[0104] The present invention relates to pharmaceutical compositions containing nanoparticles of beclosonide. The pharmaceutical compositions are preferably for parenteral administration, such as injections or topical formulations. The types of pharmaceutical compositions herein are not limited. Examples of formulations include topical ophthalmic preparations (e.g., eye drops). These preparations can be prepared according to conventional methods. The pharmaceutical compositions preferably contain a dispersion stabilizer.

[0105] Pharmaceutical compositions may contain pharmacologically acceptable carriers (additives used in formulations). Those skilled in the art can appropriately select the type of additive used in the formulation of the pharmaceutical composition, the ratio of the additive to the active ingredient, and the method used to manufacture the pharmaceutical composition, depending on the form of the composition. Additives used in formulations may be inorganic or organic, or solid or liquid. Specific examples of such substances include lactose, glucose, mannitol, dextrin, cyclodextrin, starch, sucrose, magnesium aluminum metasilicate, synthetic aluminum silicate, sodium carboxymethylcellulose, hydroxypropyl starch, calcium carboxymethylcellulose, ion exchange resins, methylcellulose, gelatin, gum arabic, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, PVA, light anhydrous silicic acid, magnesium stearate, talc, tragacanth, bentonite, magnesium aluminum silicate (veegum), titanium oxide, sorbitan fatty acid esters, sodium lauryl sulfate, glycerin, fatty acid glycerides, purified lanolin, glycerol gelatin, polysorbate, polyethylene glycol, vegetable oil, wax, liquid paraffin, white paraffin, fluorocarbons, nonionic surfactants, propylene glycol, water, benzalkonium chloride, hydrochloric acid, sodium chloride, sodium hydroxide, lactic acid, sodium, sodium monohydrogen phosphate, sodium dihydrogen phosphate, citric acid, sodium citrate, disodium edetate, For example, the pharmaceutical composition may contain one or more additives for formulation selected from POE-POP diol, PVA, hydroxypropyl methylcellulose and methylcellulose.

[0106] In one embodiment, the present invention provides a method for preparing an aqueous pharmaceutical composition containing beclosonide nanoparticles, comprising mixing a diluent and an aqueous suspension containing beclosonide nanoparticles.

[0107] When preparing pharmaceutical compositions (e.g., topical ophthalmic preparations (preferably eye drops)), the pH and osmotic pressure are not limited as long as they are acceptable for topical preparations, and are preferably pH 3 to 9.5, more preferably pH 3.5 to 9, and even more preferably pH 4 to 8. The osmotic pressure ratio of the preparation (except for ointments) to physiological saline is, for example, about 0.3 to 4.3, preferably about 0.3 to 2.2, and particularly preferably about 0.5 to 1.5. The pH and osmotic pressure can be controlled using pH control agents, tonicity agents, or salts by methods known in the art.

[0108] The pharmaceutical composition can be suitably prepared by a known method, for example, by mixing an aqueous suspension containing beclorosone dipropionate nanoparticles with the desired components in a suitable diluent such as distilled water or purified water, adjusting the above-mentioned osmotic pressure and pH value, subjecting the composition to high-pressure steam sterilization or filter sterilization under aseptic conditions, and aseptically filling it into washed sterile containers.

[0109] Methods for treating or improving complications of cataract surgery

[0110] The present invention provides a method for treating or ameliorating cataract surgery complications in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an aqueous suspension.

[0111] Examples of surgical complications include, but are not limited to, high anterior chamber cell (ACC) count, pain, impaired vision, eye inflammation, and eye infection.

[0112] In one embodiment of the present invention, the cataract surgery is uncomplicated cataract surgery or complicated cataract surgery. In one embodiment of the present invention, the cataract surgery is uncomplicated cataract surgery.

[0113] In some embodiments of the present invention, the aqueous suspension comprises 0.01 wt% to 0.2 wt%; 0.015 wt% to 0.18 wt%; 0.02 wt% to 0.16 wt%; 0.025 wt% to 0.14 wt%; 0.03 wt% to 0.12 wt%; 0.035 wt% to 0.1 wt%; 0.04 wt% to 0.08 wt%; 0.04 wt% to 0.06 wt%; 0.05 wt%; or 0.1 wt% of beclosonide. In some other embodiments of the present invention, the aqueous suspension comprises 0.05 wt% or 0.1 wt% of beclosonide.

[0114] In some embodiments of the present invention, the pharmaceutical composition is administered before, during, or after cataract surgery. In one embodiment of the present invention, the pharmaceutical composition is administered after cataract surgery.

[0115] The dosage can be appropriately determined depending on the condition and is generally administered to the eye once to six times a day, for example, once, twice, three times, four times, five times, or six times a day, with about 1 to 3 drops administered each time. In some embodiments of the present invention, the pharmaceutical composition is administered once, twice, three times, or four times a day. In some other embodiments of the present invention, the pharmaceutical composition is administered twice a day (BID) or once a day (QD).

[0116] In one embodiment of the present invention, the pharmaceutical composition is administered at least once. In one embodiment of the present invention, the pharmaceutical composition is administered on postoperative day 1 (POD 1). In one embodiment of the present invention, the pharmaceutical composition is administered on the day of cataract surgery.

[0117] In one embodiment of the present invention, the pharmaceutical composition is administered for at least one day. The administration period can be any period until the symptoms have sufficiently subsided (e.g., two weeks to one year). In some embodiments of the present invention, the pharmaceutical composition is administered for 3 to 28 days; 4 to 27 days; 5 to 26 days; 6 to 26 days; 7 to 25 days; 8 to 24 days; 9 to 23 days; 10 to 22 days; 11 to 21 days; 12 to 20 days; 13 to 19 days; 14 to 18 days; 15 to 17 days. In some other embodiments of the present invention, the pharmaceutical composition is administered for 7 days, 14 days, 21 days, or 28 days.

[0118] The dosage and frequency of administration of the pharmaceutical composition are not limited and can be appropriately selected at the physician's discretion based on the purpose of preventing deterioration / progression and / or the purpose of treating the disease to be treated, the type of disease, and the patient's condition (such as weight and age). The dosage is generally about 0.01 to 1000 mg per day (based on the weight of the active ingredient) for adults and can be administered once or several times a day.

[0119] When the aqueous pharmaceutical composition of the present invention is for topical administration, it is applied directly to a local area, such as the affected area, the area surrounding the affected area, or an organ including the affected area. When the pharmaceutical composition of the present invention is a topically administrable formulation, it can be applied daily or at any number of times after cataract surgery.

[0120] Ophthalmic compositions

[0121] The present invention provides an ophthalmic composition comprising: Nanoparticles of beclosonide propionate, wherein the average particle size of the nanoparticles is 300 nm or less and the D90 particle size of the nanoparticles is 450 nm or less; Physiologically acceptable salts; glycerin; hydrogenated soy lecithin; Anhydrous citric acid; Boric acid; EDTA; and BAK, wherein the concentration of benzalkonium chloride is less than 45 ppm, 44 ppm, 43 ppm, 42 ppm, 41 ppm, 40 ppm, 39 ppm, 38 ppm, 37 ppm, 36 ppm, 35 ppm, 34 ppm, 33 ppm, 32 ppm, 31 ppm, 30 ppm, 29 ppm, 28 ppm, 27 ppm, 26 ppm, 25 ppm, 24 ppm, 23 ppm, 22 ppm, 21 ppm, 20 ppm, 19 ppm, 18 ppm, 17 ppm, 16 ppm, or 15 ppm. In some embodiments of the present invention, the concentration of benzalkonium chloride is between 15 ppm and 45 ppm.

[0122] In some embodiments of the present invention, by using EDTA and boric acid, the BAK concentration is reduced (such as from 60 ppm to below 45 ppm. Without wishing to be bound by theory, it is believed that lower BAK concentrations are desirable because of the negative effects on corneal and eye health in general.

[0123] In some embodiments of the present invention, the ophthalmic composition comprises nanoparticles of beclosonide dipropionate, sodium chloride, hydrogenated soy lecithin, glycerin, anhydrous citric acid, polyvinyl alcohol, poloxamer 407, BAK, methylcellulose, boric acid, and EDTA.

[0124] In some embodiments of the present invention, the pH is lowered from 7 to 6 compared to conventional products. Without wishing to be bound by theory, it is believed that the lower pH may prevent and / or reduce the formation of impurities. In some embodiments, increasing the methylcellulose content also aids in eye retention time by increasing viscosity.

[0125] In some embodiments of the present invention, the ophthalmic composition comprises 0.05 wt% to 0.15 wt% of nanoparticles of beclosonide dipropionate, 0.5 wt% to 1.5 wt% of sodium chloride, 0.05 wt% to 0.15 wt% of hydrogenated soy lecithin, 0.1 wt% to 0.4 wt% of glycerol, 0.003 wt% to 0.01 wt% of anhydrous citric acid, 0.05 wt% to 0.15 wt% of polyvinyl alcohol, 0.002 wt% to 0.01 wt% of poloxamer 407, 0.003 wt% to 0.004 wt% of BAK, 0.3 wt% to 0.8 wt% of methylcellulose, 0.15 wt% to 0.35 wt% of boric acid, and 0.01 wt% to 0.07 wt% of EDTA.

[0126] The following examples are provided to help those skilled in the art to practice the present invention.

[0127] Examples

[0128] Preparation of 0.05% ophthalmic nanoparticle suspension (average particle size of about 130 nm) (Suspension 1)

[0129] 50 g of micronized becloralidone propionate (melting point: 190.0-200.0°C, FARMABIOS SpA) with an average volume-weighted mean D[4,3] (DeBrouckere mean) particle size of 2.315 mm, 550 g of sodium chloride (Tomita Salt K-30, Tomita Pharmaceutical Co., Ltd.), 50 g of hydrogenated soy lecithin (Phospholipon 90H, Lipoid GmbH), and 4 g of anhydrous citric acid (Sigma-Aldrich Co., LLC) were placed in a 5.0 L water-cooled vertical mixer (INOUE MFG., INC.) and uniformly mixed. 75 g of glycerol (Sigma-Aldrich Co., LLC) was added to the mixture while maintaining it in a dough (nanomixture) state and milling at 4±2°C for 6 hours.

[0130] The particle size distribution of the nanoparticles was measured as follows. 0.1 g of the resulting pulverized and kneaded product (dough (nanomixture)) and 5 g of a 0.01% poloxamer 407 solution (prepared from poloxamer 407, BASF SE) as a dispersant were weighed into a 50 mL screw-down bottle and uniformly dispersed using an ultrasonic device (Model VS-100III, AS ONE Corporation). 45 g of the 0.01% poloxamer 407 aqueous solution was added thereto to obtain a 50 g suspension. The particle size distribution of the resulting suspension was measured using a particle size distribution analyzer (Model ELSZ-2000ZS, Otsuka Electronics Co., Ltd.). The particle size distribution of beclosonide propionate was found to have an average particle size of 133 nm, a 10% particle size (D10) of 75 nm, a particle size distribution (D50) of 116 nm, and a 90% particle size (D90) of 184 nm.

[0131] 320 g of the pulverized and kneaded product (dough (nanomixture)) was mixed with 21.075 kg of a 0.01% poloxamer 407 solution and dispersed by an L5M-A high shear homogenizer, then transferred to a 50 L jacketed stainless steel tank and mixed with 4.2 kg of a 1.0% PVA aqueous solution (prepared from polyvinyl alcohol, Merck KGaA) to obtain a coarse dispersion, which was treated using a high-pressure homogenizer (H-20, SANWA ENGINEERING LTD.) to obtain a dispersion. To 18.75 kg (total dispersion weight of 25.6 kg) of the dispersion, 101.8 g of a 1% aqueous benzalkonium chloride (BAK) solution, 6 kg of a 2.5% methylcellulose (MC) solution containing 1.25% boric acid (BA) solution, and 300 g of a 5% EDTA-2Na 2H 2 O aqueous solution were added. 200 g of a 1M aqueous trisodium citrate solution and approximately 85 g of glycerol were then added to adjust the pH and osmolality. Water for injection was then added to a total of 30 kg to obtain a 0.05% ophthalmic nanosuspension (average particle size of 134 nm). The resulting ophthalmic suspension had a pH of 6 and an osmolality of 285 mOsmol / kg. Redispersion, sterile filtration, and filling were then performed to obtain a 0.05% beclosonide propionate ophthalmic nanosuspension.

[0132] Table 1 shows the composition of each 0.05% beclosonide dipropionate ophthalmic nanosuspension. Components composition(%) Beclosone propionate 0.054 Sodium chloride 0.59 Hydrogenated soy lecithin 0.054 glycerin 0.37 Anhydrous citric acid 0.004 PVA 0.10 Poloxamer 407 0.005 Benzalkonium chloride (BAK) 0.0036 Methylcellulose 0.5 Boric acid 0.25 <![CDATA[EDTA-2Na 2H2O]]> 0.05 Trisodium citrate appropriate amount Water for injection appropriate amount

[0133] Preparation of 0.05% placebo ophthalmic nanoparticle suspension (average particle size of approximately 130 nm) (Placebo Suspension 1)

[0134] 100 g of hydrogenated soy lecithin (Phospholipon 90H, Lipoid GmbH), 550 g of sodium chloride (TomitaSalt K-30, Tomita Pharmaceutical Co., Ltd.), and 4 g of anhydrous citric acid (Sigma-Aldrich Co., LLC) were placed in a 5.0 L water-cooled vertical mixer (INOUE MFG., INC.) and uniformly mixed. 75 g of glycerin (Sigma-Aldrich Co., LLC) was added to the mixture while maintaining it in a dough (nanomixture) state and milling at 4 ± 2°C for 6 hours.

[0135] The particle size distribution of the nanoparticles was measured as described in "Suspension 1". The particle size distribution was found to have an average particle size of 98 nm, a 10% particle size (D10) of 43 nm, a particle size distribution (D50) of 78 nm, and a 90% particle size (D90) of 158 nm.

[0136] 320 g of the pulverized and kneaded product (dough (nanomixture)) was mixed with 21.075 kg of a 0.01% poloxamer 407 solution and dispersed by a L5M-A high shear homogenizer, then transferred to a 50 L jacketed stainless steel tank and mixed with 4.2 kg of a 1.0% PVA (Merck KGaA) aqueous solution to obtain a coarse dispersion, which was treated using a high-pressure homogenizer (H-20, SANWA ENGINEERING LTD.) to obtain a dispersion. To 18.75 kg (total dispersion weight of 25.6 kg) of the dispersion was added 101.8 g of a 1% aqueous benzalkonium chloride (BAK) solution, 6 kg of a 2.5% methylcellulose (MC) solution containing 1.25% boric acid (BA) solution, and 300 g of a 5% EDTA-2Na 2H 2 O aqueous solution. 200 g of 1M trisodium citrate and approximately 85 g of glycerol were then added to adjust the pH and osmolality. Water for injection was then added to a total of 30 kg to obtain a 0.05% placebo ophthalmic nanosuspension (average particle size of 128 nm). The resulting ophthalmic suspension had a pH of 6 and an osmolality of 283 mOsmol / kg. Redispersion, sterile filtration, and filling were then performed to obtain a 0.05% placebo ophthalmic nanosuspension.

[0137] Table 2 shows the composition of each 0.05% placebo beclosonide dipropionate ophthalmic nanosuspension.

[0138] Preparation of 0.1% ophthalmic nanoparticle suspension (average particle size of about 120 nm) (Suspension 2)

[0139] 50 g of micronized becloralidone propionate (melting point: 190.0-200.0°C, FARMABIOS SpA) with a volume-weighted mean D[4,3] (De Broc mean) particle size of 2.315 μM, 550 g of sodium chloride (Tomita Salt K-30, Tomita Pharmaceutical Co., Ltd.), 50 g of hydrogenated soy lecithin (Phospholipon 90H, Lipoid GmbH), and 4 g of anhydrous citric acid (Sigma-Aldrich Co., LLC) were placed in a 5.0 L water-cooled vertical mixer (INOUEMFG., INC.) and uniformly mixed. 75 g of glycerol (Sigma-Aldrich Co., LLC) was added to the mixture while maintaining it in a dough (nanomixture) state and milling at 4±2°C for 6 hours.

[0140] The particle size distribution of the nanoparticles was measured as described in "Suspension 1". The particle size distribution of beclosonide propionate was found to have an average particle size of 121 nm, a 10% particle size (D10) of 65 nm, a particle size distribution (D50) of 103 nm, and a 90% particle size (D90) of 171 nm.

[0141] 666 g of the pulverized, kneaded product (dough (nanomixture)) was mixed with 21.075 kg of a 0.01% poloxamer 407 solution and dispersed using an L5M-A high-shear homogenizer. The mixture was then transferred to a 50 L jacketed stainless steel tank and mixed with 4.2 kg of a 1.0% aqueous PVA solution (prepared from polyvinyl alcohol, Merck KGaA) to obtain a coarse dispersion. This dispersion was then treated using a high-pressure homogenizer (H-20, SANWA ENGINEERING LTD.) to obtain a dispersion. To 18.75 kg (total dispersion weight of 25.94 kg) of the dispersion were added 101.8 g of a 1% aqueous benzalkonium chloride (BAK) solution, 6 kg of a 2.5% methylcellulose (MC) solution containing 1.25% boric acid (BA) in an aqueous solution, and 300 g of a 5% EDTA-2Na 2H 2 O solution. 1 M trisodium citrate was then gradually added until the pH reached 6. Water for injection was then added to a total of 30 kg to obtain a 0.1% ophthalmic nanosuspension (average particle size of 137 nm). The resulting ophthalmic suspension had an osmotic concentration of 474 mOsmol / kg. Redispersion, sterile filtration, and filling were then performed to obtain a 0.1% beclosonide propionate ophthalmic nanosuspension.

[0142] Table 3 shows the composition of each 0.1% beclosonide ophthalmic nanosuspension. Components composition(%) Beclosone propionate 0.11 Sodium chloride 1.2 Hydrogenated soy lecithin 0.11 glycerin 0.17 Anhydrous citric acid 0.008 PVA 0.10 Poloxamer 407 0.005 Benzalkonium chloride (BAK) 0.0036 Methylcellulose 0.5 Boric acid 0.25 <![CDATA[EDTA-2Na 2H2O]]> 0.05 Trisodium citrate appropriate amount Water for injection appropriate amount

[0143] Preparation of 0.1% placebo ophthalmic nanoparticle suspension (average particle size of approximately 110 nm) (Placebo Suspension 2)

[0144] 100 g of hydrogenated soy lecithin (Phospholipon 90H, Lipoid GmbH), 550 g of sodium chloride (TomitaSalt K-30, Tomita Pharmaceutical Co., Ltd.), and 4 g of anhydrous citric acid (Sigma-Aldrich Co., LLC) were placed in a 5.0 L water-cooled vertical mixer (INOUE MFG., INC.) and uniformly mixed. 75 g of glycerin (Sigma-Aldrich Co., LLC) was added to the mixture while maintaining it in a dough (nanomixture) state and milling at 4 ± 2°C for 6 hours.

[0145] The particle size distribution of the nanoparticles was measured as described in "Suspension 1". The particle size distribution was found to have an average particle size of 112 nm, a 10% particle size (D10) of 50 nm, a particle size distribution (D50) of 92 nm, and a 90% particle size (D90) of 175 nm.

[0146] 666 g of the pulverized, kneaded product (dough (nanomixture)) was mixed with 21.075 kg of a 0.01% poloxamer 407 solution and dispersed using an L5M-A high-shear homogenizer. The mixture was then transferred to a 50 L jacketed stainless steel tank and mixed with 4.2 kg of a 1.0% aqueous PVA solution (prepared from polyvinyl alcohol, Merck KGaA) to obtain a coarse dispersion. This dispersion was then treated using a high-pressure homogenizer (H-20, SANWA ENGINEERING LTD.) to obtain a dispersion. To 18.75 kg (total dispersion weight of 25.94 kg) of the dispersion were added 101.8 g of a 1% aqueous benzalkonium chloride (BAK) solution, 6 kg of a 2.5% methylcellulose (MC) solution containing 1.25% boric acid (BA) solution, and 300 g of a 5% aqueous EDTA-2Na 2H 2 O solution. 1 M trisodium citrate was then gradually added until the pH reached 6. Water for injection was then added to a total of 30 kg to obtain a 0.1% ophthalmic nanosuspension (average particle size of 128 nm). The resulting ophthalmic suspension had an osmotic concentration of 473 mOsmol / kg. Redispersion, sterile filtration, and filling were then performed to obtain a 0.1% placebo ophthalmic nanosuspension.

[0147] Table 4 shows the composition of each 0.1% placebo beclosonide dipropionate ophthalmic nanosuspension.

[0148] Methods for treating complications of cataract surgery

[0149] 132 participants (subjects) aged 50 and older were recruited.

[0150] Part A: Subjects with ocular inflammation on postoperative day 1 (POD 1) after routine, uncomplicated cataract surgery were randomized to receive 1 drop of Suspension 1 (N=22) or matching placebo Suspension 1 (N=23) in the study eye BID (morning and evening) for 21 days. Assessments were performed on POD 1 (baseline), (4, 8, 15, and 22).

[0151] Part B: Subjects were randomly assigned to receive Suspension 1 (N=22), Suspension 2 (N=22), or matching placebo (N=22 for placebo Suspension 1 and N=21 for placebo Suspension 2) BID for 3 days, followed by QD dosing for 11 days. Assessments were performed on POD 1 (baseline), (4, 8, 15, and 22).

[0152] Anterior chamber cell (ACC) count

[0153] Absolute anterior chamber cell count

[0154] Time frame: 22 days after surgery (Part A or B)

[0155] The number of cells in the anterior chamber of the eye was counted using slit lamp biopsy at each study visit, and the results are reported as the number of cells in a 1 mm x 1 mm area.

[0156] The meaning of ACC count is the number of dead cells. The smaller the value, the lower the number of necrotic cells. The results are shown in Figure 1 The group receiving the suspension 1 BID on POD 22 showed the lowest ACC count.

[0157] Figure 2 The percentage of subjects with an ACC count of 0 (no cell necrosis) at a given time point is shown. On POD 22, the suspension 1 BID group showed approximately 80% of subjects had no necrosis in anterior chamber cells.

[0158] Eye pain level

[0159] Time frame: 22 days after surgery (Part A or B)

[0160] Ocular pain was measured in each eye using a five-point (0 to 4) subject-reported ocular pain rating scale (0 = no pain; 4 = severe pain).

[0161] The results are shown in Figure 3 middle. Figure 3 The percentage of subjects with a pain index of 0 at each time point is shown. All suspension groups showed significantly better effects compared to the placebo group. On POD 22, 90% of the subjects in the suspension 1 BID group were pain-free.

[0162] formulations

[0163] 20 g of the pulverized and kneaded product (dough (nanomixture)) was mixed with 1.32 kg of a 0.01% poloxamer 407 solution and dispersed by an L5M-A high shear homogenizer. The mixture was then transferred to a 1 L jacketed stainless steel tank and mixed with 265 g of a 1.0% PVA aqueous solution (prepared from polyvinyl alcohol, Merck KGaA) to obtain a coarse dispersion, which was then treated with a high-pressure homogenizer (L01-YH1, SANWA ENGINEERING LTD.) to obtain a dispersion. To 1.25 kg (total dispersion volume of 1.61 kg) of the dispersion, 0.082 g, 0.062 g, 0.056 g, 0.046 g, or 0.032 g of a 10% aqueous benzalkonium chloride (BAK) solution, 400 g of a 2.5% methylcellulose (MC) solution containing 1.25% boric acid (BA) solution, and 20 g of a 5% EDTA-2Na·2H2O solution were added. 13.35 g of a 1M aqueous trisodium citrate solution and approximately 5.65 g of glycerol were then added to adjust the pH and osmolality. Water for injection was then added to a total of 2 kg to obtain a 0.05% ophthalmic nanosuspension. The resulting ophthalmic suspension had a pH of 5.7 to 6.3 and an osmolality of 265 to 270 mOsmol / kg. Then, the mixture is redispersed, sterile filtered, and filled to obtain a 0.05% beclosonide propionate ophthalmic nanosuspension.

[0164] Table 5 shows the composition of each 0.05% beclosonide ophthalmic nanosuspension.

[0165] The foregoing description of exemplary embodiments of the present invention has been presented for purposes of illustration and description only and is not intended to be exhaustive or to limit the invention to the precise form disclosed. Many modifications and variations are possible in light of the above teachings.

Claims

1. A method for treating or ameliorating complications of cataract surgery in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an aqueous suspension, wherein the aqueous suspension comprises: Nanoparticles of clobetasol propionate, wherein the average particle size of the nanoparticles is 300 nm or less and the D90 particle size of the nanoparticles is 450 nm or less; Physiologically acceptable salts; glycerin; Hydrogenated soy lecithin; and anhydrous citric acid; and Complications of the procedure included high anterior chamber cell (ACC) count or pain.

2. The method of claim 1, wherein the pharmaceutical composition is administered before, during, or after cataract surgery.

3. The method of claim 1, wherein the surgical complications further comprise impaired vision, eye inflammation and / or eye infection. The method of claim 1 , wherein the cataract surgery is uncomplicated cataract surgery.

5. The method of claim 1, wherein the aqueous suspension comprises 0.01 wt% to 0.2 wt% of beclosonide.

6. The method of claim 1, wherein the pharmaceutical composition is administered once, twice, three times or four times daily.

7. The method of claim 1, wherein the pharmaceutical composition is administered on post-operative day 1 (POD 1).

8. The method of claim 1, wherein the pharmaceutical composition is administered at least once.

9. The method of claim 1, wherein the pharmaceutical composition is administered for 3 to 28 days.

10. The method of claim 1, wherein the nanoparticles are prepared by mixing beclosonide, the physiologically acceptable salt, glycerol, hydrogenated soy lecithin, and anhydrous citric acid.

11. The method of claim 10, wherein the nanoparticles are prepared by further mixing beclosonide propionate, the physiologically acceptable salt, glycerol, hydrogenated soy lecithin and anhydrous citric acid with a surface modifier.

12. The method of claim 11, wherein the surface modifier comprises a surfactant, an agglomeration inhibitor, a viscosity regulator and / or a dispersion stabilizer.

13. The method of claim 12, wherein the surface modifier is a dispersion stabilizer.

14. The method according to claim 13, wherein the dispersion stabilizer is polyoxyethylene polyoxypropylene glycol and / or polyvinyl alcohol. The method of claim 11 , wherein the surface modifier is the viscosity modifier.

16. The method of claim 14, wherein the viscosity modifier is one or more substances selected from the group consisting of methylcellulose, hydroxypropyl methylcellulose and polyvinyl alcohol.

17. The method of claim 14, wherein the aqueous suspension comprises 1 to 10 mg / mL of the viscosity modifier.

18. The method of claim 1, wherein the pharmaceutical composition is administered in the form of eye drops.

19. An ophthalmic composition comprising: Nanoparticles of beclosonide propionate, wherein the average particle size of the nanoparticles is 300 nm or less and the D90 particle size of the nanoparticles is 450 nm or less; Physiologically acceptable salts; glycerin; hydrogenated soy lecithin; Anhydrous citric acid; Boric acid; Ethylene diamine tetraacetic acid (EDTA); and Benzalkonium chloride (BAK), in, The concentration of benzalkonium chloride was less than 45 ppm.

20. The ophthalmic composition according to claim 19, comprising the nanoparticles of beclosonide dipropionate, sodium chloride, hydrogenated soy lecithin, glycerin, anhydrous citric acid, polyvinyl alcohol, poloxamer 407, BAK, methylcellulose, boric acid and EDTA.

21. The ophthalmic composition of claim 19, comprising 0.05 wt% to 0.15 wt% of nanoparticles of beclosonide, 0.5 wt% to 1.5 wt% of sodium chloride, 0.05 wt% to 0.15 wt% of hydrogenated soy lecithin, 0.1 wt% to 0.4 wt% of glycerol, 0.003 wt% to 0.01 wt% of anhydrous citric acid, 0.05 wt% to 0.15 wt% of polyvinyl alcohol, 0.002 wt% to 0.01 wt% of poloxamer 407, 0.003 wt% to 0.004 wt% of BAK, 0.3 wt% to 0.8 wt% of methylcellulose, 0.15 wt% to 0.35 wt% of boric acid, and 0.01 wt% to 0.07 wt% of EDTA.

Images