Corticosteroid nanosuspensions and uses thereof

Abstract

A suspension formulation of nanoparticles of clobetasol propionate is described. The suspension can be therapeutically used for treating skin and eye burns; wound healing is enhanced; preventing or reducing hypertrophic scabs / keloids; the traditional Chinese medicine composition is used for treating allergic rhinitis / nasosinusitis, asthma, inner ear diseases including hearing loss, tinnitus or dizziness, tenosynovitis, tendinitis, puncturitis or arthritis.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480029391.1 (22) Application Date 2024.04.30 (30) Priority Data 63 / 463,113 2023.05.01 US (85) PCT International Application Entering National Phase Date 2025.10.30 (86) PCT International Application Application Data PCT / US2024 / 026982 2024.04.30 (87) PCT International Application Publication Data WO2024 / 228993 EN 2024.11.07 (71) Applicant Anmum Pharmaceuticals Development Company Address USA (72) Inventors L. Wong D.J. Nunes J.B. Cook W.WC. Leo (74) Patent Agency Beijing Zhucheng Law Firm 11313 Patent Attorneys Chen Yanjuan and Wang Yanbo (51) Int.Cl. A61K 31 / 56 (2006.01) A61K 47 / 69 (2006.01) (54) Invention Title: Corticosteroid Nanoparticle Suspension and Its Uses (57) Abstract: Describes a suspension formulation of clobetasol propionate nanoparticles. The suspension is therapeutically applicable to the treatment of skin and eye burns; to enhance wound healing; to prevent or reduce hypertrophic scars / keloids; and to treat allergic rhinitis / sinusitis, asthma, inner ear disorders including hearing loss, tinnitus, or vertigo, tenosynovitis, tendinitis, enthesitis, or arthritis. Claims (2 pages), Description (27 pages), Drawings (8 pages), CN 121038796 A, 2025.11.28, CN 1 21 03 87 96 A: 1. A method for treating a subject with skin or eye burns, the method comprising applying a sterile suspension of clobetasol propionate nanoparticles to the burn site. 2. A method for treating a subject suffering from abnormal wound healing, hypertrophic scarring, or keloids, the method comprising contacting the patient's skin wound, scar, or keloid with a sterile suspension of clobetasol propionate nanoparticles. 3. A method for treating a subject suffering from allergic rhinitis / sinusitis or asthma, the method comprising contacting the patient's nasal and sinus mucosa or airways with a suspension of clobetasol propionate nanoparticles. 4. A method for treating a subject suffering from an inner ear disorder, specifically hearing loss, tinnitus, or vertigo, the method comprising contacting a suspension of clobetasol propionate nanoparticles with a tympanic membrane or delivering a suspension of clobetasol propionate nanoparticles to the patient's inner ear or nasal mucosa.5. A method for treating a subject suffering from tenosynovitis, tendinitis, or enthesitis, the method comprising injecting a sterile suspension of clobetasol propionate nanoparticles into the synovial space or tendon / ligament enthesium of the patient. 6. A method for treating a subject suffering from arthritis, the method comprising injecting a sterile suspension of clobetasol propionate nanoparticles into the joint of the patient. 7. The method of claims 1, 2, 3, and 4, wherein the suspension of clobetasol propionate nanoparticles is applied using a spray bottle, dropper, or aerosol device, or via injection with a syringe and needle. 8. The method of claims 5 and 6, wherein the sterile suspension of clobetasol propionate nanoparticles is injected with a syringe and needle. 9. The method of claims 1 and 2, wherein the suspension of clobetasol propionate nanoparticles reduces complications of burns or abnormal wound healing, including inflammation, pain, abnormal granulation, scarring, contractures, deformities, pigmentation, or visual impairment. 10. The method of claims 3 to 6, wherein the suspension formulation of clobetasol propionate nanoparticles reduces complications of allergic rhinitis / sinusitis, asthma, inner ear disorders, tenosynovitis, tendinitis, enthesitis, or arthritis. 11. The method of claim 4, wherein the suspension formulation of clobetasol propionate nanoparticles reduces complications of inner ear disorders, including tinnitus, vertigo, and hearing loss. 12. The method of claims 5 and 6, wherein the suspension formulation of clobetasol propionate nanoparticles reduces complications of tenosynovitis, tendinitis, enthesitis, or arthritis, including pain and / or discomfort or decreased mobility. 13. The method of any one of claims 1 to 6, wherein the suspension formulation of clobetasol propionate nanoparticles reduces inflammation. 14. The method of claims 5 and 6, wherein the suspension formulation of clobetasol propionate nanoparticles improves joint, tendon, or ligament function. 15. The method of any one of claims 1 to 14, wherein a suspension formulation of clobetasol propionate nanoparticles is applied once or more daily to burned skin or eyes, nose, respiratory tract, nasal mucosa, tympanic membrane, inner ear, synovial space, ligament, or joint for up to 52 weeks. 16. A droplet, spray, mist, aerosol, or injection formulation comprising clobetasol propionate, wherein the clobetasol propionate is formulated as a suspension of nanoparticles. 17. The droplet, spray, mist, aerosol, or injection formulation of claim 16, further comprising sodium chloride, hydrogenated soybean, lecithin, anhydrous citric acid, glycerin, poloxamer 407, polyvinyl alcohol (PVA), boric acid, disodium edetate dihydrate, benzalkonium chloride, methylcellulose, or trisodium citrate, or combinations thereof.Claims 1 / 2 Page 2 CN 121038796 A 18. The droplet, spray, mist, aerosol, or injectable formulation of claim 16, wherein it is in a sterile form. 19. The droplet, mist, spray, aerosol, or injectable formulation of claim 16, further comprising an antioxidant, an antimicrobial agent, an anti-inflammatory agent, an anesthetic, an analgesic, a lubricant, a flavoring agent, or a combination thereof. 20. A unit dose configured for administration by injection or by eye drops, said unit dose comprising clobetasol propionate, wherein said clobetasol propionate is formulated as a sterile suspension of nanoparticles. 21. The unit dose of claim 20, further comprising sodium chloride, hydrogenated soybean, lecithin, anhydrous citric acid, glycerin, poloxamer 407, polyvinyl alcohol (PVA), boric acid, disodium edetate dihydrate, benzalkonium chloride, methylcellulose, or trisodium citrate, or a combination thereof. 22. The unit dose of claim 20, further comprising an antioxidant, an antimicrobial agent, an anesthetic, an analgesic, or a combination thereof. 23. The method of claim 2, wherein the spray or droplet of claim 16 is applied to the surface of the subject's skin or eye. 24. The method of claim 2, wherein the injection of claim 16 is injected into a hypertrophic scar or keloid of the subject. 25. The method of claim 3, wherein the spray or droplet of claim 16 is applied to the nasal and sinus mucosa of the subject. 26. The method of claim 3, wherein the spray or droplet of claim 16 is inhaled into the lungs. 27. The method of claim 4, wherein the spray or droplet of claim 16 is applied to the tympanic membrane of the ear or to the nasal mucosa. 28. The method of claim 4, wherein the unit dose of claim 20 is injected intratympanically. 29. The method of claim 5, wherein the unit dose of claim 20 is injected into the synovial space or tendon / ligament attachment point of the subject. 30. The method of claim 6, wherein the unit dose of claim 20 is injected into a joint of the subject. Claims 2 / 2 Page 3 CN 121038796 A Corticosteroid Nanoparticle Suspension and Its Use

[0001] Field of the Invention The present invention described herein relates to a suspension formulation of nanoparticles of corticosteroids such as clobetasol propionate, and to methods for treating skin or eye burns, abnormal wound healing, allergic rhinitis / sinusitis, asthma, inner ear disorders, tenosynovitis, tendinitis, enthesitis, and arthritis. Background Art

[0002] Treatment of Burns Burns are injuries to the skin or other tissues (including tissues in the eyes) caused by a number of reasons that damage cellular structures.The severity of burns varies depending on the extent of tissue damage, sometimes resulting in widespread tissue inflammation, cell death, and necrosis. Treatment of skin burns depends on the type and severity of the burn. In more severe cases, intensive treatment is required to improve the healing process and reduce complications such as hypertrophic scarring, skin contractures, keloids, and deformities.

[0003] Ocular burns are particularly problematic because the damage can cause irreversible damage to the cornea and other structures in the eye, significantly affecting vision. The cornea is the main refractive tissue in the front of the eye. It is typically avascular and consists of a thin anterior epithelium, a thin posterior endothelium, and a highly complex stroma, which accounts for approximately 90% of the corneal thickness. Corneal transparency is crucial for allowing light to enter the eye and reach the photoreceptor cells in the retina at the back of the eyeball. Corneal transparency is achieved through a cell-free matrix, which is a highly ordered structure with several types of collagen fibers and other extracellular matrix molecules. When this complex stromal tissue is damaged by mechanical injury, inflammation, edema, or neovascularization, the cornea becomes increasingly cloudy and vision is significantly impaired. Therefore, to protect vision, it is necessary to reduce and / or prevent inflammation, edema, neovascularization, and structural disturbances of the matrix proteins in the stromal tissue following burns. Current treatments are not entirely effective in restoring those structures to normal.

[0004] Regardless of the type of burn, the healing process should be closely monitored, as inflammation and abnormal recovery can lead to long-term complications. For example, in the case of skin burns, hypertrophic scarring, skin contractures, and abnormal pigmentation can significantly impact a patient's quality of life. Ocular burns can affect the conjunctiva, sclera, cornea, and even extraocular tissues such as the eyelids, and may be an ophthalmic emergency requiring rapid assessment and intervention to protect vision by minimizing inflammation and the buildup of substances that impede light entry into the eye. There is an ongoing need for treatments and approaches to burns, including those focusing on reducing scarring, accelerating the healing process, and restoring and protecting vision.

[0005] Treatment of Abnormal Wound Healing Skin wounds typically heal in four stages: post-hemorrhagic inflammation, cell proliferation, and then remodeling. Scar tissue forms during the remodeling stage. Typically, a small epidermal wound heals by fusing with surrounding tissue to form new skin. Deeper wounds within and below the dermis require more extensive connective tissue remodeling and collagen deposition to heal, which can result in permanent scarring. Some types of skin injury can lead to prolonged and excessive inflammation and are associated with abnormal wound healing. There is also a genetic predisposition to excessive scarring and keloid formation. Current treatments for hypertrophic scars and keloids, including laser therapy, injections of anti-proliferative drugs such as bleomycin and 5-fluorouracil, and cryotherapy, have limited efficacy.The effectiveness of conventional steroid injections is limited because this suboptimal treatment requires repeated painful injections, which do not prevent the progression of scarring, cosmetic damage, and decreased mobility. Therefore, more effective treatments are needed to prevent cosmetic scarring.

[0006] Treatment of Allergic Rhinitis / Sinusitis Allergic rhinitis and sinusitis (rhinitis / sinusitis) are common types of allergies that can be caused by seasonal or non-seasonal allergens. Acute hypersensitivity reactions to allergens are characterized by sneezing, runny nose, itching of the eyes, nose, and palate, nasal and sinus congestion, postnasal drip, cough, airway constriction, and other debilitating symptoms. While conventional treatments can manage mild symptoms of allergic rhinitis / sinusitis, in some cases, these treatments are insufficient, and interventions are needed to prevent serious complications such as airway narrowing. There is a persistent need for therapeutic agents and treatments for allergic rhinitis / sinusitis.

[0007] Treatment of Asthma Asthma is a chronic disease affecting the lungs, characterized by inflammation, airway narrowing, and bronchoconstriction, causing wheezing, chest tightness, shortness of breath, and coughing. The etiology of asthma is not fully understood, but there may be a genetic predisposition to environmental triggers such as allergens, tobacco smoke or other toxic gases and airborne particulate matter. Exposure to these factors leads to the release of inflammatory mediators, causing bronchospasm, airway edema, and abnormal mucus production, resulting in characteristic asthma symptoms. In some cases, conventional steroid preparations can be used, but they generally must be co-administered with β-adrenergic receptor agonists to reduce airway inflammation and asthma symptoms. However, in many cases, current medications are insufficient to prevent asthma attacks, thus requiring excessively high doses and co-administration with long-acting β-agonists. Therefore, there is a persistent need for therapeutic agents and treatments for asthma.

[0008] Inner Ear Disorders Inner ear disorders can present as hearing loss, vertigo, and tinnitus, affecting many adults, especially the elderly. When tinnitus, hearing loss, and vertigo occur together, they are called Ménière's disease. These inner ear disorders are often accompanied by endolymphatic hydrops, which is the expansion of the endolymphatic compartments of the inner ear. The U.S. Food and Drug Administration has not approved a drug treatment to prevent or treat hearing loss, vertigo, or tinnitus. Because the causes of these symptoms are not well understood, many proposed treatments have been ineffective or have limitations or serious side effects. Therefore, there is a continued need for treatments and methods for hearing loss, tinnitus, and vertigo.

[0009] Treatment of tenosynovitis, tendinitis, enthesitis, and arthritis Tenosynovitis is an inflammation of the tendon within the synovial sheath, while enthesitis is an inflammation of the tendon or ligament attached to bone. As the tendon moves within its sheath or at its attachment to bone, it may be stimulated by trauma or repetitive or excessive movement, causing inflammation, pain, and potentially severe limitation of function.Chronic inflammation can lead to swelling and / or fibrosis in the tendon sheath, reducing space in the tendon and causing conditions such as "trigger finger" or nerve compression, for example, in the case of carpal tunnel syndrome. Repetitive joint movements or impacts from vibrating tools can trigger inflammatory processes in the tendon sheath or enthesium, which can occur in the hand or foot and affect individuals in many types of occupations.

[0010] Medical treatment for tenosynovitis, tendinitis, and enthesitis includes the use of splints to reduce tendon movement and injections of corticosteroids. In some cases, surgery is required when pain and impaired tendon function do not respond to rest and anti-inflammatory treatment, but surgery can be very painful and may result in additional fibrosis and long-term complications.

[0011] Arthritis is the most common cause of disability in the United States, causing joint pain and inflammation that affects more than 50 million people of all ages, including children. Osteoarthritis and rheumatoid arthritis are the two most common types of arthritis, but there are other types such as ankylosing spondylitis, gout, and psoriatic arthritis. Osteoarthritis is the most common type of arthritis. Although it can occur at any age following joint damage, it typically develops in middle-aged or older adults. Osteoarthritis initially affects the smooth cartilage lining of the joint, limiting movement and causing pain and stiffness. Continued damage to the cartilage lining leads to swelling of the joint and can potentially cause osteophyte formation and impaired joint function. Rheumatoid arthritis is less common than osteoarthritis. It is an immune-mediated damage to joint tissue that begins in the synovial lining of the joint and causes pain, swelling, and joint deformity.

[0012] Symptoms of arthritis include joint pain, tenderness, and stiffness; inflammation within and around the joint; limited joint movement; warm red skin over the affected joint; and weakness and muscle atrophy. There is no cure for arthritis, although current treatments can help slow joint damage, including lifestyle modifications, medications, physical therapy, and surgery. Treatment options depend on the severity of the arthritis, symptoms, and the patient's overall health, but in many cases, symptoms and signs do not improve. Surgery, including bone fusion to stabilize the joint and reduce movement-induced pain, or artificial joint replacement to preserve joint function and movement, remains the only option in some severe arthritis cases. Therefore, there is a persistent need for treatments and methods for osteoarthritis, rheumatoid arthritis, and other less common types of arthritis. Summary of the Invention

[0013] In one illustrative embodiment of the invention, compositions comprising suspensions of corticosteroids and / or glucocorticoid nanoparticles are described herein, as well as their use in the manufacture of medicaments and compositions for treating diseases. Illustrated diseases include skin or eye burns, abnormal wound healing, allergic rhinitis / sinusitis, asthma, inner ear disorders, tenosynovitis, tendinitis, enthesitis, and arthritis.

[0014] It has been found herein that skin or eye burns, abnormal wound healing, allergic rhinitis / sinusitis, asthma, inner ear disorders (including hearing loss, tinnitus, and vertigo), tenosynovitis, tendinitis, enthesitis, and arthritis (including osteoarthritis and rheumatoid arthritis) can be treated more effectively with nanoparticle suspensions of glucocorticoids such as (but not limited to) clobetasol propionate. These glucocorticoids are formulated as nanoparticle suspensions that can be applied topically, orally, by intestinal injection, intratympanic injection; injected into joints, synovial spaces, or around tendon entheses; or applied as a spray, aerosol, or droplets into the nasal cavity, respiratory system, or external auditory canal.

[0015] In another embodiment, compositions comprising nanoparticle suspensions of glucocorticoids are described herein for the treatment of skin or eye burns, abnormal wound healing, allergic rhinitis / sinusitis, asthma, inner ear disorders (including hearing loss, vertigo, and tinnitus), tenosynovitis, tendinitis, enthesitis, and arthritis.

[0016] In another embodiment, a method for treating skin or eye burns, abnormal wound healing, allergic rhinitis / sinusitis, asthma, and inner ear disorders is described herein. The method includes administering an effective amount of a glucocorticoid nanosuspension to a subject in need.

[0017] In another embodiment, the use of a composition comprising a glucocorticoid nanosuspension in the manufacture of a medicament for treating skin or eye burns, abnormal wound healing, allergic rhinitis / sinusitis, asthma, inner ear disorders, tenosynovitis, tendinitis, enthesitis, and arthritis is described herein.

[0018] In another embodiment, packaging articles and kits comprising a composition comprising a glucocorticoid nanosuspension are described herein. The packaging articles and kits include instructions for using the nanosuspension to treat skin or eye burns, abnormal wound healing, allergic rhinitis / sinusitis, asthma, inner ear disorders, tenosynovitis, tendinitis, enthesitis, and arthritis.

[0019] Corticosteroids have been used clinically to treat hearing loss, tinnitus, and vertigo, but with limited effectiveness. Glucocorticoid receptors are expressed in the inner ear, including hair cells and spiral ganglion neurons. Glucocorticoids are believed to protect hearing and treat inner ear diseases through multiple mechanisms of action, including reducing inner ear inflammation and reactive oxygen species, activating cell survival pathways, and reducing apoptosis in hair cells and spiral ganglion neurons. However, current corticosteroid treatment paradigms are suboptimal due to limited efficacy, which may be related to several factors, including insufficient potency of corticosteroids and insufficient concentrations of corticosteroids in the inner ear due to poor delivery or limited penetration.As described herein, embodiments of the invention include, as described on page 3 / 27 of specification 6 CN 121038796 A, the use of nanoparticle formulations containing clobetasol propionate (the most potent glucocorticoid used in clinical practice) to increase the penetration and concentration of this glucocorticoid in inner ear tissues and fluids.

[0020] Embodiments of the invention include droplets, sprays, mists, or aerosols for treating various types of tissue burns, such as burns caused by heat sources, chemical exposure, sunlight exposure, or mechanical injury. The droplets, sprays, mists, and aerosols are optionally included or incorporated therein with an applicator, burn dressing, etc. In other embodiments, the droplets, sprays, mists, and aerosols minimize or alleviate pain, improve healing, reduce scarring, and / or improve vision.

[0021] Embodiments of the invention include injection into hypertrophic scars or keloids to reduce connective tissue accumulation, skin deformities, contractures, and improve cosmetic appearance. Embodiments of the present invention include applying a spray, mist, aerosol, or droplet into the nasal cavity to treat allergic rhinitis / sinusitis or inhaling it into the lungs to treat asthma. In other embodiments, the spray, mist, aerosol, or droplet reduces symptoms of allergic rhinitis / sinusitis or prevents, reduces, or stops asthma attacks.

[0022] Embodiments of the present invention include applying a spray or droplet to the tympanic membrane through the external auditory canal to treat inner ear disorders, specifically, hearing loss, tinnitus, and vertigo. Embodiments of the present invention include intratympanic injection or intranasal application of a spray, aerosol, or droplet to treat inner ear disorders, specifically, hearing loss, tinnitus, and vertigo. Without being bound by theory, this paper considers that the failure of current drug treatments is due to insufficient efficacy and limited penetration into the inner ear tissue, and that the fluid and nanoparticle suspensions of highly effective glucocorticoids (e.g., clobetasol propionate) described herein have greater penetration into the inner ear.

[0023] Embodiments of the present invention include aseptic injection into the synovial space to treat tenosynovitis, tendinitis, or injection into or around the tendon / ligament attachment point to treat enthesitis. Embodiments of the present invention include aseptic injection into an intra-articular region to treat arthritis.

[0024] In another illustrative embodiment, a suspension formulation in the form of a spray, mist, aerosol, injectable, or droplet is described herein, containing about 0.025% to about 0.15% w / v clobetasol propionate nanoparticles. The suspension formulation may include additional agents, including (but not limited to) preservatives, antibacterial agents, and / or disinfectants.

[0025] In another embodiment, a method for manufacturing a nanoparticle suspension of corticosteroids and / or glucocorticoids (e.g., clobetasol propionate) is described herein.

[0026] It should be understood that the compositions, kits, and methods described herein may include clobetasol propionate, or one or more alternative and / or additional corticosteroids and / or glucocorticoids, including (but not limited to) dexamethasone, difluprednate, triamcinolone, betamethasone dipropionate, prednisolone, etc.

[0027] Other features and advantages of the invention described herein will become apparent from the specific embodiments described herein, in conjunction with the accompanying drawings, which further illustrate the invention by means of non-limiting examples. Brief Description of the Drawings

[0028] Figure 1 shows a flowchart of the steps for producing an illustrative suspension formulation of clobetasol propionate nanoparticles.

[0029] Figures 2A-2D show the efficacy of 0.1% CPN after ocular alkali burns in New Zealand White rabbits. Statistical differences compared to the medium are indicated by * (p<0.05).

[0030] Figures 3A-3C show the efficacy of 0.1% CPN in treating skin burn wounds in Yorkshire-cross pigs. Statistical differences compared to the untreated control are indicated by * (p<0.05).

[0031] Figures 4A-4D show the efficacy of 0.1% CPN in a rabbit ear hypertrophic scar model. Statistical differences compared to the untreated control are indicated by * (p<0.05).

[0032] Figures 5A-5B show the efficacy of 0.1% CPN in a collagen-induced arthritis (CIA) model in male Lewis rats. Statistical differences compared to the medium are indicated by * (p<0.05). Detailed Description

[0033] The following illustrative clauses set forth further embodiments of the invention described herein: 1. A method for treating a subject suffering from skin or eye burns, abnormal wound healing, allergic rhinitis / sinusitis, asthma, or inner ear disorders (including, but not limited to, hearing loss, tinnitus, or vertigo); said method comprising applying a suspension of clobetasol propionate nanoparticles to said subject’s skin or eye burns, skin wounds, nasal or sinus mucosa (for allergic rhinitis / sinusitis or inner ear disorders), airway and lung tissue, or tympanic membrane of the ear.

[0034] 2. The method of Clause 1, wherein said formulation is applied using a dropper, spray bottle, or device, aerosol delivery device, or inhaler.

[0035] 3. The method of Clause 1 or 2, wherein the skin or eye burn is sunburn, radiation burn, radioactive burn, electrical burn, boiling liquid burn, abrasion, chemical burn, burn caused by fire, flame, explosive, fuel or lubricant ignition, high-temperature combustion of battlefield weapons, or a combination thereof; and optionally, wherein treatment of eye burn includes long-term improvement of vision and / or visual acuity following the eye burn.

[0036] 4. The method of Clause 1 or 2, wherein the abnormal wound healing is caused by burns, inflammation, infection, or trauma including surgical incisions, and optionally, wherein the treatment includes reducing and / or preventing hypertrophic scarring.

[0037] 5. The method of Clause 1 or 2, wherein the allergic rhinitis / sinusitis or asthma is caused by chemical exposure, particulate exposure or seasonal allergens; and the inner ear disorder is caused by noise, trauma or ototoxic chemicals, and optionally, wherein the treatment of allergic rhinitis / sinusitis or asthma includes the treatment or prevention of bronchospasm with reversible obstructive airway disease, management of nasal symptoms of perennial non-allergic rhinitis, relief of symptoms of seasonal and perennial allergic rhinitis, or any combination thereof.

[0038] 6. The method of any of the preceding clauses, wherein the suspension formulation of said clobetasol propionate nanoparticles reduces complications of skin or eye burns, abnormal wound healing, allergic rhinitis / sinusitis, asthma, or inner ear disorders, including (but not limited to) inflammation, pain, discomfort, swelling, corneal opacity, abnormal granulation and / or scarring, contractures, hypertrophic scarring, keloids, rhinitis, nasal and sinus congestion, airway obstruction and respiratory distress, hearing loss, tinnitus, and vertigo.

[0039] 7. The method of any of the preceding clauses, wherein the suspension formulation of said clobetasol propionate nanoparticles improves wound healing, relieves allergic rhinitis / sinusitis or asthma, or reduces hearing loss, tinnitus, or vertigo.

[0040] 8. A method for treating a subject suffering from a tendon / synovial disorder, including (but not limited to) tendinitis, synovitis, enthesitis, or arthritis; said method comprising introducing a sterile suspension of clobetasol propionate nanoparticles into the tympanic cavity, synovial space, tendon enthesitis, or joint of said subject, and optionally, said treatment comprising reducing inflammation around the joints, tendons, and / or ligaments of said subject.

[0041] 9. A method for treating a subject suffering from an inner ear disorder, including (but not limited to) hearing loss, tinnitus, or vertigo; said method comprising introducing a sterile suspension of clobetasol propionate nanoparticles into the tympanic cavity, synovial space, tendon enthesitis, or joint of said subject, and optionally, said treatment comprising reducing cochlear hair cell loss, protecting hearing, or a combination thereof.

[0042] 10. The method of clause 8 or 9, wherein the preparation is introduced by injection, for example by using a syringe and a needle.

[0043] 11. The method of clause 8 or 9, wherein the inner ear disorder is caused by noise, trauma, or ototoxic chemicals. Specification 5 / 27 pages 8 CN 121038796 A

[0044] 12. The method of clause 8 or 9, wherein the tendon / synovial disorder is caused by mechanical vibration, overuse, autoimmune disease, or a combination thereof, and / or is not caused by an infectious agent or infection, or is at least not partially caused by an infectious agent or infection.

[0045] 13. The method of clause 8 or 9, wherein the arthritis is osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, gouty arthritis, or psoriatic arthritis, or a combination thereof, and / or is not caused by an infectious agent or infection, or is at least not partially caused by an infectious agent or infection.

[0046] 14. The method of any one of clauses 8 to 13, wherein the suspension formulation of clobetasol propionate nanoparticles reduces complications of inner ear disorders or tendon / synovial disorders or arthritis, including (but not limited to) hearing loss, tinnitus, vertigo, inflammation, swelling, pain, discomfort, and decreased mobility.

[0047] 15. The method of any one of clauses 8 to 14, wherein the suspension formulation of clobetasol propionate nanoparticles reduces hearing, tinnitus, vertigo, or improves joint or tendon function.

[0048] 16. The method of any one of the preceding clauses, wherein the suspension formulation of clobetasol propionate nanoparticles is administered once or more daily for up to 52 weeks; or at least once daily for 1 to 4 weeks.

[0049] 17. A droplet, spray, mist, aerosol, or injectable formulation comprising clobetasol propionate, wherein the clobetasol propionate is formulated as a suspension of nanoparticles.

[0050] 18. Droplets, sprays, mists, aerosols, or injectable formulations as described in Clause 17, used in any of the methods described in Clauses 1 to 16.

[0051] 19. Droplets, sprays, mists, aerosols, or injectable formulations as described in Clauses 1 to 16 and / or used in any of the methods described in Clauses 1 to 16, further comprising sodium chloride, hydrogenated soybean lecithin, anhydrous citric acid, glycerol, poloxamer 407, polyvinyl alcohol (PVA), boric acid, disodium edetate dihydrate, benzalkonium chloride, methylcellulose, or sodium citrate (e.g., trisodium citrate), or combinations thereof.

[0052] 20. Droplets, sprays, mists or aerosols or injectable formulations of any of the methods of any of the provisions of 17 to 19 and / or used in any of the methods of the provisions of 1 to 16, which further comprise antioxidants, antimicrobial agents, anesthetics, analgesics, lubricants, flavorings or combinations thereof.

[0053] 21. A unit dose configured for administration via transdermal, transmucosal, ocular, or injectable route; said unit dose comprising clobetasol propionate, wherein said clobetasol propionate is formulated as a sterile suspension of nanoparticles.

[0054] 22. The unit dose of clause 21, used in any of the methods of clauses 1 to 16.

[0055] 23. The unit dose of clause 21 or 22 and / or used in any of the methods of clauses 1 to 15, further comprising sodium chloride, hydrogenated soybean lecithin, anhydrous citric acid, glycerol, poloxamer 407, polyvinyl alcohol (PVA), boric acid, disodium edetate dihydrate, benzalkonium chloride, methylcellulose, or sodium citrate (e.g., trisodium citrate), or combinations thereof.

[0056] The term "implementation" is generally used to refer to illustrative examples of the invention. An embodiment may describe one or more distinguishing features, structures, and / or characteristics of the invention, and does not necessarily describe every single feature, structure, and / or characteristic of the invention. The term “aspect” generally refers to a particular feature, structure, or characteristic of the invention described herein. It should be understood that these aspects may appear alone or in combination; however, in each case these aspects may be optional and not necessarily included in the invention.

[0057] Unless otherwise defined, the terms used herein, including all technical and scientific terms, should be interpreted as having their usual meaning in the art, including in the context of this disclosure and in the specific context in which each term is used.

[0058] The use of examples anywhere in this specification (including examples of any terms discussed herein) is merely illustrative and not intended to further limit the scope and meaning of this disclosure or any exemplary terms. Similarly, this disclosure is not limited to the various embodiments given in this specification.

[0059] The terms “active agent,” “active ingredient,” “active compound,” “active component,” “active pharmaceutical ingredient,” or “API” each generally refer to a substance, compound, chemical, or molecule that has biological activity or otherwise induces biological, physiological, or pharmacological effects on a subject to which it is administered. In other words, "active agent" or "active ingredient" refers to one or more components of a composition attributable to all or part of the composition's effect. A glucocorticoid may be the primary active agent, or in other words, the composition component attributable to all or part of the composition's effect. An active agent may be a secondary agent, or in other words, the composition component attributable to additional and / or other effects of the composition.

[0060] The terms "effective amount" and "therapeutic effective amount" generally refer to the amount of a specified component sufficient to achieve the desired biological and / or therapeutic outcome.The result may be a reduction or improvement in the signs, symptoms, or cause of a disease, or any other desired change in a biological system. When the desired result is a therapeutic response, it should be understood that the effective amount will vary depending on the following: the specific disease or symptom to be treated or alleviated, the age, sex, weight, general health and diet of the subject to be treated, the time of administration, the excretion rate, possible combinations of drugs, the administration regimen of the formulation, the size or location of the area to be treated and the form of administration, the severity of the disease condition, such as burn wounds, abnormal wound healing, allergic rhinitis / sinusitis, asthma, inner ear disorders (specifically, hearing loss, tinnitus, or vertigo), tenosynovitis, tendinitis, enthesitis, or arthritis, the type and extent of the response to be achieved, whether other agents are used, the method of administration, etc., all of which can be readily determined by one of ordinary skill in the art.

[0061] The terms “treating / treatment” or “alleviation” generally refer to both therapeutic treatment and preventive or preventive measures, wherein the aim is to prevent or alleviate (reduce) a target pathological condition or disease. If, after receiving a therapeutic amount of nanoparticle suspension according to the methods described herein, a subject exhibits an observable and / or measurable reduction or absence of one or more signs and symptoms of a specific disease or condition, then the subject is successfully “treated” with the disease, ailment, or condition. For example, in the case of burns, treatment or prevention may include a reduction in the size or severity of the burn wound, a reduction in pain, a faster healing process, and / or improved healing (e.g., reduced scarring / granulation / pigmentation). Other examples include: for abnormal wound healing, treatment or prevention may include reduction in scar tissue size, faster healing process and / or improved healing; for ocular burns, treatment or prevention may include reduction in corneal opacity and improved vision; for allergic rhinitis / sinusitis, treatment or prevention may include reduction in nasal discharge and symptoms such as itching and nasal congestion; for asthma, treatment or prevention may include reduction in bronchoconstriction, wheezing, shortness of breath, chest tightness, pain or cough; for inner ear disorders, treatment or prevention may include improvement in hearing, vertigo and tinnitus; for tenosynovitis, tendinitis, enthesitis and arthritis, treatment or prevention may include reduction in pain, swelling and deformity and improvement in mobility.

[0062] The term “administration” generally refers to the introduction of a predetermined amount of a substance into or onto a subject by some suitable method. The compositions disclosed herein can be applied via any of the common routes, including topically, such as by applying droplets to the eyes, spraying, or by applying small droplets to the surface of the eyes, skin, or mucous membranes, or by applying to the tympanic membrane through the external auditory canal, or by injecting into the synovial space, tendon or ligament attachment point, joint, or scar, or by injecting into the tympanic cavity.

[0063] As used herein, the term “pharmaceutical acceptable” means that the composition is sufficient to achieve a therapeutic effect without harmful side effects and can be readily determined based on the type, severity and location of the burn wound, abnormal wound healing, allergic rhinitis / sinusitis, asthma, inner ear disorder (specifically, hearing loss, tinnitus or vertigo), tenosynovitis, tendinitis, enthesitis or arthritis, the subject’s age, weight, health status, sex, drug sensitivity, administration mode, administration frequency, duration of treatment, drugs used in combination with or concurrently with the compositions disclosed herein, and other factors known in medicine.

[0064] The terms “burn” or “burn condition” generally refer to a wide range of illnesses, including those caused by: for example, excessive exposure to radiation (e.g., radioactive and solar radiation that causes sunburn), thermal radiation, welding flash, fire, electrical discharge, chemical exposure, friction, contact with hot objects (e.g., cooking equipment components) or hot fluids (e.g., boiling water, steam, hot oil, flames, etc.), battlefield burns, etc. These burns and burn conditions, although arising from different sources, share common symptoms and disease progression.

[0065] The term “allergic rhinitis / sinusitis” generally refers to a range of such conditions, including those caused by seasonal exposure to allergens (e.g., pollen) and those caused by exposure to chemicals or particulates that may not be seasonal.

[0066] The term asthma generally refers to a range of conditions, including those caused by exposure to allergens, irritant gases, pollutants, and chemicals, as well as symptoms caused by exposure to cold or dry air or exercise / sports activities.

[0067] The term "inner ear disorder" generally refers to a condition defined as hearing loss, tinnitus, or vertigo, which may have many causes, including (but not limited to) noise and endolymphatic hydrops.

[0068] The term "tenosynovitis" generally refers to a range of such conditions, including those caused by infectious and non-infectious causes. Non-infectious causes include autoimmune disorders, overuse of diseased tissues, and idiopathic diseases for which the cause of the condition is not yet determined.

[0069] The term "enthesitis" generally refers to a range of such conditions, including those caused by infectious and non-infectious causes. Non-infectious causes include injury, overuse, diseases such as ankylosing spondylitis, and idiopathic diseases for which the cause of the condition is not yet determined.

[0070] The term "arthritis" generally refers to a range of such conditions, including those caused by infectious and non-infectious causes. Non-infectious causes include osteoarthritis, gout, and autoimmune disorders such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and systemic lupus erythematosus.

[0071] The term “subject” generally refers to a host animal to be treated with the compositions and methods described herein, such as (but not limited to) humans and animals, including companion animals and livestock such as dogs, cats, rabbits, birds, cattle, horses, monkeys, sheep, goats, reptiles, hamsters, guinea pigs, and other animals, whether domesticated or not. Illustratively, a subject includes a host animal that has or is diagnosed with skin or eye injuries, burns, allergic rhinitis / sinusitis or asthma, inner ear disorders (including hearing loss, tinnitus, or vertigo), tenosynovitis, tendinitis, enthesitis, or arthritis.

[0072] The term “granulation tissue” generally refers to new connective tissue and microvessels that form in a wound during the healing process. Granulation tissue typically grows from the sides and bottom of a wound and is capable of filling wounds of almost any size. Instances of granulation tissue can be seen in healing wounds caused by surgical procedures. Its histological appearance is characterized by the proliferation of fibroblasts and new, thin-walled capillaries (angiogenesis) and infiltrating inflammatory cells in a loose extracellular matrix of proteins (e.g., collagen).

[0073] The term “corneal opacification” is generally used to describe a condition in which corneal opacity or scarring results in a loss of corneal transparency, thereby preventing light from reaching the retina at the back of the eye. As a result, images may become distorted or blurred, leading to decreased or complete vision loss. Corneal transparency depends on the proper arrangement of collagen fibrils in the cornea and the absence of edema. Changes in the spacing and type of collagen fibrils and edema may be caused by burns or contact with harmful chemicals on the surface of the eye.

[0074] The terms “glucocorticoids” or “glucocorticoid steroids” generally refer to a class of corticosteroids, which are steroid hormones. Glucocorticoids are corticosteroids that bind to glucocorticoid receptors, which are present in the cells of almost every vertebrate. Glucocorticoids are part of the stress response and play a role in the feedback mechanism of the immune system, reducing certain aspects of immune function, such as inflammation. Therefore, they are commonly used to treat conditions caused by an overactive immune system (e.g., allergies, asthma, steroid-sensitive skin diseases, and autoimmune diseases). Clobetasol propionate is a highly selective and potent glucocorticoid receptor agonist. Specification 8 / 27 pages 11 CN 121038796 A

[0075] The term "clobetasol propionate" generally refers to the following molecules.

[0076] The term "nano-grinding" generally refers to a method of reducing the particle size of an agent to a nanoscale by grinding using polymer or ceramic media or other proprietary techniques. Nano-grinding can be used to formulate poorly water-soluble APIs into small particles with a large surface area, thereby enhancing API solubility.

[0077] The term "nanoparticles" generally refers to small particles with an average particle size typically in the range of 1 to 300 nanometers.Compared to their correspondingly larger material counterparts, nanoparticles, which are invisible to the human eye as individual particles, can exhibit significantly different physical and chemical properties.

[0078] The term "nanoparticle suspension" generally refers to a suspension containing active agent particles of nanoparticle size in a suspension. For example, glucocorticoids are hydrophobic and can be provided in the form of an aqueous suspension. However, aqueous suspensions of glucocorticoid compounds containing particles larger than nanoparticles can be problematic because larger steroid particles can precipitate or clump over time, requiring patients to shake the container before use to ensure uniform dispersion of the active ingredient in the liquid phase. Even with shaking, larger particles in the suspension are prone to aggregate or cluster, causing the particle diameter of the drug to increase over time and resulting in a loss of uniformity of the suspension contents. Due to these problems, it is difficult to achieve uniform dispersion of larger particles and consistent application of the active ingredient. In addition, the reduced surface area of ​​larger particles decreases the dissolution rate of the API, thus reducing its tissue penetration and therapeutic efficacy. However, the present invention described herein does not have these aggregation or agglomeration problems.

[0079] As used herein, the particle size distribution of the suspended nanoparticles in the formulation is determined using dynamic light scattering with a commercially available instrument such as an Otsuka ELSZ-2000ZS particle size analyzer. This analyzer generates a histogram of the particle size distribution, from which D10, D50, D90, and the average particle size are determined.

[0080] The term “metered spray” or “MDTS” generally refers to a device that delivers a drug to the surface of the skin, mucous membrane, or airway and allows for sustained absorption into the tissue. It functions in a manner similar to a transdermal patch or topical gel. The drug is delivered and triggered by a device placed close to the skin or mucous membrane, causing it to release a light spray of a proprietary formulation containing drug molecules to form an invisible reservoir of the drug. Just as it would from a patch, the drug is then stably absorbed over a predetermined time period.

[0081] The term “scar” generally refers to connective tissue that marks the site of healing of skin or other tissue following injury such as burns or other trauma. Scars are the body's natural way of healing and replacing lost or damaged skin or other tissue. Scars are typically composed of fibrotic tissue. Hypertrophic scars are an abnormal response to wound healing in which excessive connective tissue and collagen deposition occurs in the original wound area, resulting in an abnormally raised scar. The term "keloid" generally refers to an abnormal type of scar that extends beyond the initial wound area. In contrast to hypertrophic scars, keloid scars develop slowly and extend beyond the original wound area, resulting in a large, abnormal scar that is much larger than the original wound area. These types of scars can cause severe, permanent damage to appearance. Specification 9 / 27 pages 12 CN 121038796 A

[0082] The term "contraction" generally refers to an abnormal event that occurs when a large area of ​​skin is damaged and lost, resulting in scarring.Scar formation pulls the skin edges together, causing the skin around the injured area to become taut. Contractures can also occur when there is chronic inflammation at tendon, tendon sheath, tendon / ligament attachment point, or joint. The treatment option for contracture release is surgery, in which the scar or chronically inflamed tissue is cut to release the tension. In some cases, skin replacement can be performed using donor tissue that matches the texture, color, and flexibility.

[0083] It should be understood that in each of the cases disclosed herein, a description of the range of any variable is a description of the range itself, each individual member of the range, and each possible subrange of the variable. For example, a description of n as an integer from 0 to 8 describes the range, individual and alternative values ​​of 0, 1, 2, 3, 4, 5, 6, 7, and 8, such as n being 0, or n being 1, or n being 2, etc. Additionally, a description of n as an integer from 0 to 8 also describes each subrange, each of which can be the basis for another embodiment, such as n being an integer from 1 to 8, 1 to 7, 1 to 6, 2 to 8, 2 to 7, 1 to 3, 2 to 4, etc.

[0084] It should also be understood that, unless otherwise indicated, a statement of a numerical value necessarily reflects its relative precision. For example, stating a number with a specified precision based on significant figures necessarily includes a range of values ​​that will match the number after appropriate rounding. For example, it should be understood that stating the number 1 with a single significant figure appropriately refers to a range of values ​​from 0.5 to 1.4. Similarly, it should be understood that stating the number 1.0 with two significant figures appropriately refers to a range of values ​​from 0.95 to 1.04. The relative precision of a numerical value can be further indicated by using the term “about” to indicate that the modified number has a lower precision.

[0085] As used herein, the term “about” generally means, when used with a numerical value or limit, that the number is approximate and, as stated, includes a range of values. For example, a real number stated with a single significant figure will, by definition, include a so-called rounding range; a number about 5 will include at least the range 4.5 to 5.4, since each of those values ​​is rounded to 5. For real numbers expressed with additional significant figures, it should also be understood that the corresponding rounding range applies to the last significant figure. It should be understood that integers include at least values ​​±1 (for single-digit numbers), ±10 (for two-digit numbers), etc. Depending on the context and variables, the term “about” is also interpreted to consider a range based on a percentage of the stated number; for example, about 5 is interpreted to include 5 ± 10% or, in some cases, 5 ± 5%. Despite the foregoing, it should be understood that, unless otherwise indicated, a range of values ​​should not be interpreted to include the negative range of the stated positive number, and vice versa. Additionally, depending on the context, unless otherwise indicated, a stated number should not be interpreted to include zero values ​​when used in conjunction with other components.

[0086] It should be understood that all numerical names, such as pH, temperature, time, concentration, and molecular weight, including ranges, are approximate values ​​according to convention in the art.

[0087] Unless otherwise indicated, percentages (%) of ingredients and components in the formulations described herein, expressed as % w / v, refer to grams per deciliter (g / dL).

[0088] As used herein, the transitional phrase “consistently of…” means that the scope of the corresponding composition, unit dose, method, or use should be understood to include the specified compound or the described steps, and those compounds or steps that do not materially affect the fundamental and novel characteristics of the invention described herein. For example, it should be understood that the methods described herein, consisting essentially of a single compound or genus of compounds, represent a single therapy for the described disease. Although such a single therapy may include co-administration of one or more carriers, mediators, diluents, adjuvants, excipients, etc., and combinations thereof, and / or include co-administration of one or more additional active pharmaceutical ingredients, it should be understood that those additional active pharmaceutical ingredients are for the treatment of diseases and / or symptoms different from those of the underlying conditions described herein, such as skin or eye burns, abnormal wound healing, allergic rhinitis / sinusitis, asthma, inner ear disorders, tenosynovitis, tendinitis, enthesitis, or arthritis itself. Additional active pharmaceutical ingredients may include, for example, active ingredients for treating pain, accompanying bacterial infections, cough, congestion, etc.

[0089] In embodiments that include a list of alternatives that may be included alone or in various combinations, it should be understood that the list also describes a list of each individual alternative and all possible subsets of those alternatives. Specification 10 / 27 pages 13 CN 121038796 A

[0090] Many known and useful compounds used in formulations, etc., can be found in Remington's Pharmaceutical Sciences (13th edition), Mack Publishing, Easton, PA (Standard Reference for Various Types of Administration). As used herein, the term "formulation" means a combination of at least one active ingredient with one or more other ingredients, often referred to as excipients, which may be active or inactive on their own. It should also be understood that the formulations described herein may or may not refer to pharmaceutically acceptable compositions for administration to humans or animals and may include compositions as intermediates, for example for storage or research purposes.

[0091] Conventional topical formulations of corticosteroids have been proposed for the treatment of burns. (See Brown et al., Journal of Burn Care & Research, Vol. 39, Supplement 1, April 2018, pp. 239-240). However, the use of these conventional agents on damaged skin tissue can cause pain and problems. More severe tissue damage (such as third and fourth-degree burns) often results in significant loss of skin tissue and fluid exudation.In these cases, conventional formulations may not adequately cover the damaged tissue area and ensure sufficient penetration of clobetasol propionate into the target area without causing significant pain and discomfort. Furthermore, these conventional formulations are intended for common skin conditions (e.g., allergies, inflammatory conditions, or autoimmune disorders). Therefore, those formulations may contain excipients, such as ethanol, which is included to improve the solubility of corticosteroids, but when exposed to burn wounds, can cause severe pain, hinder drug exposure or wound healing, and / or be incompatible with certain treatments, including those for ocular burns.

[0092] Although some glucocorticoids have been used to treat allergic rhinitis / sinusitis and asthma, the formulations described herein and / or the use of glucocorticoids such as clobetasol propionate are considered herein to offer new treatment options. For example, the formulations described herein allow for the use of smaller volumes of sprays or injections. When injection sites are limited, such as in the case of a synovial sheath, a smaller injection volume has the potential benefit of reducing post-injection pain. In addition, when conventional formulations are insufficient to improve symptoms, the formulations described herein using glucocorticoids (e.g., clobetasol propionate) with threshold activity levels can be applied directly to the tympanic membrane or tympanic cavity via the external auditory canal as a spray or ear drops, or injected into the nasal mucosa to treat hearing loss, tinnitus, or vertigo.

[0093] Clobetasol propionate nanoparticle suspension The sterile suspension of clobetasol propionate nanoparticles allows for delivery as droplets, uniform sprays, mists, aerosols, or injections. As droplets, sprays, or aerosols, it can be applied to wound areas, nasal cavities, or inhaled into the lungs, or applied to the tympanic membrane in the ear canal to achieve uniform coverage while avoiding direct contact. The sterile suspension of clobetasol propionate nanoparticles can also be applied as droplets to the eyes, nasal cavity, or ear canal.

[0094] In other embodiments, a suspension formulation of clobetasol propionate nanoparticles is described. Some of the suspensions described herein are optimized for the treatment of burn complications and can be uniformly applied by spraying onto the injured area or by droplet application. Spray or aerosol application can cover a large surface area and avoid the pain associated with mechanical application required to rub conventional ointments / lotions onto burns, thus providing efficiency and comfort. Nanoparticle suspensions allow clobetasol propionate to penetrate effectively into burn tissue, thus exhibiting improved clinical efficacy and safety characteristics compared to conventional formulations.

[0095] Some of the suspension formulations described herein are optimized for the treatment of abnormal wound healing and can be applied by spraying or dripping onto the abnormally healed wound or by injection into the wound. Nanoparticle suspensions allow clobetasol propionate to penetrate effectively into tissue, thus exhibiting excellent clinical efficacy and tolerability characteristics compared to conventional formulations.

[0096] Certain nanoparticle suspension formulations described herein have been optimized for the treatment of allergic rhinitis / sinusitis and asthma, inner ear disorders (specifically, hearing loss, tinnitus, or vertigo), tenosynovitis, tendinitis, enthesitis, and arthritis, and can be applied to the nasal and sinus mucosa by spray, aerosol, or droplets, or by inhalation into the lungs, or by application to the tympanic membrane through the external auditory canal, or by injection into the tympanic cavity, or by injection into the synovial space, enthesium, or intra-articular region. Nanoparticle specification 11 / 27 pages 14 CN 121038796 A The suspension allows clobetasol propionate to penetrate effectively into tissues, thus exhibiting excellent clinical efficacy and tolerability characteristics compared to conventional formulations.

[0097] Nanoparticle suspension formulations can be produced by dispersing nano-milled clobetasol propionate, optionally together with a mixture of one or more excipients, in an aqueous formulation. The nano-milling method described herein allows clobetasol propionate to be formulated into a suspension with an average particle size distribution in the range of less than 250 nm, making individual particles invisible to the naked eye. The formulation is a milky white liquid that feels smooth and comfortable when applied to the skin, eyes, or mucous membranes (e.g., nose or lungs) or injected into the tympanic cavity or synovial space, attachment points, joints, or scars. The clobetasol propionate nanoparticle suspension described herein allows clobetasol propionate to penetrate tissues effectively from the high surface area nanoparticles upon surface application or injection. The nanoparticle formulations described herein are designed to optimally deliver therapeutic amounts of clobetasol propionate to the target tissue. Additionally, these aqueous spray formulations are compatible with damaged tissues with exudates when ointments, lotions, and / or creams are not available. As an injectable formulation, the clobetasol propionate nanoparticle suspension described herein allows for the injection of more concentrated drug in smaller volumes and provides an extended duration of action.

[0098] In another embodiment, compositions of nanoparticle suspensions in the form of sprays or injectable formulations are described herein as transdermal, transepithelial, transmembrane, transmucosal, and transcorneal sprays, droplets, or aerosols. These sprays, droplets, or aerosols can be applied to the skin, eyes, nasal cavity and sinus membranes, or respiratory airways to treat diseases or injuries without the negative effects of conventional ointments / lotions.

[0099] In another embodiment, injectable formulations are described herein. These injectable formulations can be injected into tendons / ligaments, synovial spaces, or intra-articular spaces to treat diseases or injuries without the negative effects of conventional ointments / lotions.

[0100] In another embodiment, nanoparticle suspension formulations of clobetasol propionate in the form of sprays, droplets, mists, aerosols, or injections are prepared as sterile liquids suitable for filling into sterile spray bottles, eye drop bottles, aerosol devices, or inhalers; or into injectable vials or ampoules; or into pre-filled syringes for easy use.

[0101] In another embodiment, the local spray, droplet, aerosol, or injectable formulation of the clobetasol propionate nanoparticle suspension contains clobetasol propionate at a concentration ranging from about 0.01% to about 0.25% w / v (inclusive) or from about 0.025% to about 0.15% w / v (inclusive). In another embodiment, the concentration is about 0.025%, about 0.05%, about 0.075%, about 0.1%, about 0.125%, or about 0.15% w / v.

[0102] In another embodiment, the local spray, droplet, aerosol, or injectable formulation of the clobetasol propionate nanoparticle suspension contains sodium chloride at a concentration ranging from about 0.05% to about 3.0% w / v, or from about 0.15% to about 1.5% w / v. In another embodiment, the concentration is about 0.6%, about 0.8%, or about 1.2% w / v.

[0103] In another embodiment, the local spray, droplet, aerosol, or injectable formulation of the clobetasol propionate nanoparticle suspension contains lecithin at a concentration of about 0.01% to about 0.5% w / v, or about 0.025% to about 0.25% w / v. In another embodiment, the concentration is about 0.025%, about 0.05%, about 0.075%, about 0.1%, about 0.15%, about 0.2%, or about 0.25% w / v.

[0104] In another embodiment, the lecithin is hydrogenated soybean lecithin. In another embodiment, the lecithin is derived from egg yolk, marine sources (including seaweed and kelp), milk, rapeseed, cottonseed, and sunflower oil. In another embodiment, the lecithin is hydrolyzed lecithin.

[0105] In another embodiment, the local spray, droplet, aerosol, or injectable formulation of the clobetasol propionate nanoparticle suspension contains citric acid at a concentration ranging from about 0.001% to about 0.4% w / v, or from about 0.001% to about 0.012% w / v. In another embodiment, the concentration is about 0.002%, about 0.004%, about 0.006%, about 0.008%, or about 0.01% w / v.

[0106] In another embodiment, the local spray, droplet, aerosol, or injectable formulation of the clobetasol propionate nanoparticle suspension contains glycerol at a concentration ranging from about 0.04% to about 0.6% w / v, or from about 0.08% to about 0.32%. In another specification, page 12 / 27, 15 CN 121038796 A, the concentration is about 0.08%, about 0.12%, about 0.16%, about 0.20%, about 0.24%, about 0.28%, or about 0.32% w / v.

[0107] In another embodiment, the local spray, droplet, aerosol, or injectable formulation of the clobetasol propionate nanoparticle suspension contains a nonionic surfactant at a concentration ranging from about 0.002% to about 0.05% w / v, or from about 0.0025% to about 0.025%. In another embodiment, the concentration is about 0.0025%, about 0.005%, about 0.01%, about 0.015%, about 0.02%, or about 0.025% w / v.

[0108] In another embodiment, the nonionic surfactant is poloxamer 407. In another embodiment, the nonionic surfactant is polysorbate, polysorbate 20, polysorbate 80, sorbitol, sorbitol monolaurate, sorbitol monostearate, sorbitol tristearate, stearyl alcohol, surfactant, or any combination thereof, including combinations with poloxamer 407.

[0109] In another embodiment, the local spray, droplet, aerosol, or injectable formulation of the clobetasol propionate nanoparticle suspension contains a thickener at a concentration in the range of about 0.01% to about 2% w / v, or about 0.025% to about 0.25% w / v. In another embodiment, the concentration is about 0.025%, about 0.05%, about 0.075%, about 0.1%, about 0.15%, about 0.2%, or about 0.25% w / v.

[0110] In another embodiment, the thickener is polyvinyl alcohol (PVA), agar, albumin, alginate, casein, cetyl alcohol, cholic acid, deoxycholic acid, diacetyl tartrate, egg yolk glycerin, gum, Irish moss (carrageenan), monoglycerides, diglycerides, monostearate, sucrose esters, stearoyl lactate, propylene glycol (including its esters), and any combination thereof.

[0111] In another embodiment, the local spray, droplet, aerosol, or injectable formulation of the clobetasol propionate nanoparticle suspension contains boric acid at a concentration in the range of about 0.0% to about 0.5% w / v, more specifically, about 0% to about 0.25% w / v. In another embodiment, the concentration is about 0.0%, about 0.05%, about 0.1%, about 0.15%, about 0.2%, or about 0.25% w / v.

[0112] In another embodiment, the local spray, droplet, aerosol, or injectable formulation of the clobetasol propionate nanoparticle suspension contains edetate disodium dihydrate (EDTA) at a concentration ranging from about 0.0% to about 0.3% w / v, or from about 0.0% to about 0.15% w / v. In another embodiment, the concentration is about 0.0%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, or about 0.05% w / v.

[0113] It has been unexpectedly found here that the combination of boric acid and EDTA improves the tissue penetration of the formulations described herein. In another embodiment, the aqueous suspension of nanoparticles comprising boric acid and EDTA described herein provides a higher tissue concentration (e.g., peak concentration Cmax) of an active pharmaceutical molecule, such as clobetasol propionate, at an equivalent administered dose. In another embodiment, the aqueous suspension of nanoparticles comprising boric acid and EDTA described herein does not exhibit a long-term loss of therapeutic exposure to an active pharmaceutical molecule, such as clobetasol propionate, and maintains a significant half-life in tissue.

[0114] The suspension formulations described herein optionally include a preservative. Benzalkonium chloride (BAC) is an antimicrobial agent with a long history of use in pharmaceutical formulations to maintain product sterility. In conventional formulations, BAC levels generally need to be around 0.1% w / v to be effective as a preservative. However, these high concentrations of BAC often cause irritation or inflammation. It has been unexpectedly discovered here that, when combined with certain other excipients, such as boric acid and EDTA, BAC levels can be minimized to avoid irritation and inflammation. When combined with boric acid and EDTA, lower levels of BAC can maintain antimicrobial efficacy. It has been unexpectedly discovered that, when combined with boric acid and EDTA, BAC is reduced to less than 0.006% to about 0.004% or about 0.003% or less, maintaining antimicrobial efficacy and serving as an effective preservative for the formulations described herein.

[0115] In another embodiment, a topical spray, droplet, aerosol, or injectable formulation of a suspension of clobetasol propionate nanoparticles contains benzalkonium chloride at a concentration ranging from about 0.0% to about 0.03% w / v, or from about 0.0% to about 0.01% w / v. In another embodiment, the concentration is about 0.0%, about 0.002%, about 0.003%, about 0.0036%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, or about 0.01% w / v.

[0116] Additional preservatives may be included at concentrations that effectively inhibit microbial growth, UV light and / or oxygen-induced decomposition of the composition components, etc. When one or more preservatives are included, each or a combination thereof may be in the range of about 0.01% w / v to about 2% w / v. In another embodiment, the preservative may include phenol, benzyl alcohol, phenoxyethanol, propylparaben, methylparaben, benzoic acid, sorbic acid, bronidiol, or propylene glycol, or a combination thereof.

[0117] In another embodiment, the local spray, droplet, aerosol, or injectable formulation of the clobetasol propionate nanoparticle suspension contains methylcellulose at a concentration ranging from about 0.00% to about 3.0% w / v, or from about 0.0% to about 2.0% w / v. In another embodiment, the concentration is about 0.0%, about 0.1%, about 0.2%, about 0.5%, about 0.75%, about 1.0%, about 1.5%, or about 2.0% w / v.

[0118] It has been unexpectedly found herein that higher concentrations of methylcellulose improve the retention of drug molecules at local target tissue sites through the formulations described herein. In another embodiment, the aqueous suspension of nanoparticles comprising higher concentrations of methylcellulose described herein provides a higher tissue concentration (e.g., peak concentration Cmax) of the active drug molecule, such as clobetasol propionate, at an equivalent administered dose. In another embodiment, the aqueous suspension of nanoparticles comprising a higher concentration of methylcellulose described herein provides longer therapeutic exposure to active pharmaceutical molecules such as clobetasol propionate, as indicated by a longer half-life in target tissue.

[0119] In another embodiment, the topical spray, droplet, aerosol, or injectable formulation of the clobetasol propionate nanoparticle suspension contains sodium citrate (e.g., trisodium citrate) in concentrations ranging from about 0.01% to about 0.8% w / v to adjust the pH of the nanosuspension to an appropriate range, for example, from about 4.5 to about 6.5.

[0120] The formulations described herein may also include more than one additional therapeutic compound as needed, depending on the indication being treated (e.g., skin or eye burns). The additional therapeutic compounds generally exhibit complementary activities that do not adversely affect the activity of the other components. Illustrated therapeutic compounds for treating burns, infected tenosynovitis, or infected arthritis may be used as part of a combination as antimicrobial agents.Other therapeutic agents that can be used as combination therapy compounds to treat burn wounds include silver sulfadiazine, penicillin or penicillin derivatives (e.g., amoxicillin, including when combined with a beta-lactamase inhibitor, such as amoxicillin-clavulanate), cephalosporins (e.g., cephalexin), fluoroquinolones (e.g., ciprofloxacin), tetracyclines (e.g., doxycycline), macrolides (e.g., erythromycin), aminoglycosides (e.g., gentamicin), oxazolidinones (e.g., linezolid), and glycopeptides. (For example, vancomycin, daptomycin, fusidic acid, clindamycin, trimethoprim-sulfamethoxazole, metronidazole, daptomycin, linezolid, rifampin, bacitracin, neomycin, polymyxin B or E, nystatin, amphotericin B, echinocandin (e.g., caspofungin), triazoles (e.g., fluconazole), or combinations thereof. Other therapeutic agents that can be used to treat ocular burns include nonsteroidal anti-inflammatory drugs or antimicrobial agents and combinations thereof.

[0121] In another embodiment, antimicrobial agents for treating skin or eye burns include (but are not limited to) silver sulfadiazine, penicillin or penicillin derivatives (e.g., amoxicillin, including when combined with a β-lactamase inhibitor, such as amoxicillin-clavulanate), cephalosporins (e.g., cephalexin), fluoroquinolones (e.g., ciprofloxacin), tetracyclines (e.g., doxycycline, see page 14 / 27 of the specification, CN 121038796 A), macrolides (e.g., erythromycin), aminoglycosides (e.g., gentamicin), oxazolidinones (e.g., linezolid), glycopeptides (e.g., vancomycin), daptomycin, fusidic acid, clindamycin, trimethoprim-sulfamethoxazole, metronidazole, Daptomycin, linezolid, rifampin, bacitracin, neomycin, polymyxin B or E, nystatin, amphotericin B, echinocandin (e.g., caspofungin), triazole (e.g., fluconazole), or combinations thereof.

[0122] In another embodiment, antimicrobial agents for treating allergic rhinitis / sinusitis and asthma with secondary infections include (but are not limited to) penicillin or penicillin derivatives (e.g., amoxicillin, including when combined with a β-lactamase inhibitor, such as amoxicillin-clavulanate), cephalosporins (e.g., cephalexin), fluoroquinolones (e.g., levofloxacin), tetracyclines (e.g., doxycycline), macrolides (e.g., erythromycin), clindamycin, trimethoprim-sulfamethoxazole, or combinations thereof, doxycycline, trimethoprim-sulfamethoxazole, ciprofloxacin, penicillin, or combinations thereof.

[0123] In another embodiment, the antimicrobial agent for treating infected tendons or joints includes (but is not limited to) penicillin or penicillin derivatives (e.g., dicloxacillin, including when combined with a β-lactamase inhibitor, such as amoxicillin-clavulanate), cephalosporins (e.g., cephalexin), fluoroquinolones (e.g., ciprofloxacin), tetracyclines (e.g., doxycycline), carbapenems (e.g., meropenem, including when combined with a β-lactamase inhibitor, such as meropenem-vaborbactam), aminoglycosides (e.g., gentamicin), oxazolidinones (e.g., linezolid), glycopeptides (e.g., vancomycin), daptomycin, fusidic acid, clindamycin, trimethoprim-sulfamethoxazole, rifampin, or combinations thereof.

[0124] In another embodiment, the described aqueous suspension optionally includes a local anesthetic (e.g., lidocaine), and / or a suitable antimicrobial agent may be incorporated into the formulation to further reduce pain, provide comfort and reduce the risk of infection.Anesthetics that can be used as part of a combination with clobetasol propionate include (but are not limited to) lidocaine, pramoxine, phenol, prilocaine, benzocaine, dibucaine, menthol, methyl salicylate, zinc acetate, camphor, tetracaine, pentafluoropropane, tetrafluoroethane, or any combination thereof.

[0125] The suspensions of nanoparticles containing clobetasol propionate disclosed herein may also include pharmaceutically acceptable carriers, excipients, or diluents. Illustrative excipients are those with a “Generally Recognized As Safe” (GRAS) designation. For example, preservatives, such as antioxidants (e.g., ascorbic acid, sorbic acid, or alpha-lipoic acid), and antimicrobial agents may be included. Other components, in addition to the therapeutic active ingredient and the components that are the primary effectors of penetration into the skin, eyes, inner ear, epithelium, or synovium, may include those components provided for cosmetic purposes (e.g., menthol or other fragrances) and components that affect the physical state of the composition (e.g., lubricants in the case of intra-articular or synovial interstitial injection). These components may be present in very small or large percentages in the composition.

[0126] The disclosed suspension containing clobetasol propionate nanoparticles may be formulated in combination with the aforementioned pharmaceutically acceptable carriers to various dosage forms. For example, for topical application by means of a spray (including aerosol sprays for inhalation or spraying) or droplets, the pharmaceutical composition may be formulated in a liquid form that can be sprayed onto a subject's burn wound, or, for example, applied as droplets to the surface of the skin or eyes, or applied to the ear or nose, or, for example, for injectable use, the pharmaceutical composition may be formulated in a liquid form that can be injected into the tympanic cavity, or injected into a subject's keloid or hypertrophic scar, or injected into an inflamed synovial interstitial space, tendon / ligament attachment point, or joint.

[0127] The formulations described herein may be sterile. Sterile formulations are illustratively prepared by filtration through a sterile filter membrane before or after preparation of the spray, droplet, liquid, or injectable formulation, or by other methods known in the art, including (but not limited to) pasteurization and gamma irradiation. Specification 15 / 27 pages 18 CN 121038796 A

[0128] Formulations according to the subject matter described herein may be packaged in, for example, multipurpose or single-use packaging, including, for example, tubes, pumps, containers or bottles, vials, cans, jars, boxes, bags, or in injectable forms, for example, multiple-use or single-use packaging or pre-filled syringes. Single-dose cartridges and packages containing a once-daily dose or other suitable amount of the topical delivery formulation or injection may be prepared. Single-dose, unit-dose, and once-daily single-use containers of formulations are also provided.

[0129] In some embodiments, a therapeutic agent (e.g., a suspension of nanoparticles containing clobetasol propionate for treating skin or eye burns, abnormal wound healing, allergic rhinitis / sinusitis and asthma, inner ear disorders (specifically, hearing loss, tinnitus, or vertigo), tenosynovitis, tendinitis, enthesitis, or arthritis) is incorporated into a cartridge. In another embodiment, the cartridge may contain (but is not limited to) one or more single-chamber or multi-chamber spray bottles, any form of inhaler, dropper, or vial / ampoule, or pre-filled syringe for administering one or more therapeutic compounds described herein (including clobetasol propionate). In various embodiments, the cartridge may contain a pharmaceutical composition for topical or injectable administration, including by applying droplets, sprays, aerosols, mists, or injections containing one or more therapeutic compounds, at least one of which is clobetasol propionate for administration to a subject. In this regard, therapeutic compounds can be formulated by applying a spray or droplets to the skin, eyes, nasal and sinus mucosa, inhaling into the lungs, applying to the tympanic membrane, injecting into the tympanic cavity, or injecting into hypertrophic scars, keloids, synovial spaces, tendon / ligament attachment points, or intra-articular sites. In all these and other embodiments, the kit may contain one or more spray bottles, any form of inhaler, dropper or vial / ampoule or pre-filled syringe, instructions, and / or packaging materials according to any of the foregoing.

[0130] In another embodiment, the method of use includes the application of a therapeutic compound containing clobetasol propionate (e.g., an aqueous suspension of nanoparticles containing clobetasol propionate for treating skin or eye burns, abnormal wound healing, allergic rhinitis / sinusitis and asthma, inner ear disorders (specifically, hearing loss, tinnitus or vertigo), tenosynovitis, tendinitis, enthesitis or arthritis) for a duration of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In another embodiment, the pause or discontinuation period may last for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer.

[0131] In another embodiment, the therapeutic compound (a suspension of nanoparticles containing clobetasol propionate) may be administered multiple times a day, daily, half a week, weekly, bi-weekly, or monthly. One or more initial doses may be greater than or less than subsequent doses.

[0132] In another embodiment, a therapeutically effective amount of the suspension of nanoparticles containing clobetasol propionate disclosed herein for treating a subject with a burn wound reduces the size or severity of the burn wound site by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0133] In another embodiment, a therapeutically effective amount of the suspension of nanoparticles containing clobetasol propionate disclosed herein for treating subjects with ocular burn wounds improves vision by, for example, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0134] In another embodiment, a therapeutically effective amount of a suspension of nanoparticles containing clobetasol propionate disclosed herein for treating patients with abnormal wound healing (pages 16 / 27, 19 CN 121038796 A) reduces the size or severity of hypertrophic scars or keloids by, for example, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0135] In another embodiment, a therapeutically effective amount of the suspension of nanoparticles containing clobetasol propionate disclosed herein for treating a subject suffering from allergic rhinitis / sinusitis or asthma reduces mucosal or airway inflammation by, for example, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0136] In another embodiment, a therapeutically effective amount of the suspension of nanoparticles containing clobetasol propionate disclosed herein for treating subjects with inner ear disorders improves symptoms of hearing loss, tinnitus, or vertigo by, for example, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0137] In another embodiment, a therapeutically effective amount of the suspension of nanoparticles containing clobetasol propionate disclosed herein for treating a subject suffering from tenosynovitis, tendinitis, enthesitis, or arthritis reduces tendon, ligament, or joint inflammation by, for example, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0138] In another embodiment, symptoms or complications associated with skin or eye burns, abnormal wound healing, allergic rhinitis / sinusitis and asthma, inner ear disorders, tenosynovitis, tendinitis, enthesitis, or arthritis (e.g., hypertrophic granulation and unstable scarring, keloid formation, visual impairment, nasal congestion and discharge, airway inflammation, hearing loss, tinnitus, vertigo, joint pain, tendon enthesitis pain, or “trigger finger”) are reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% after application of the formulation.

[0139] In another embodiment, application of the formulation described herein reduces the healing and recovery time of burns, abnormal wound healing, allergic rhinitis / sinusitis and asthma, inner ear disorders (specifically, hearing loss, tinnitus or vertigo), tenosynovitis, tendinitis, enthesitis or arthritis by 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 100%.

[0140] In another embodiment, application of the formulation described herein reduces pain and / or discomfort caused by burns, tenosynovitis, tendinitis, enthesitis, or arthritis by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0141] In another embodiment, application of the formulation described herein improves mucosal edema and inflammation and reduces bronchoconstriction caused by allergic rhinitis / sinusitis or asthma by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0142] In another embodiment, a suspension containing nanoparticles of clobetasol propionate reduces the frequency of side effects or complications associated with burn wounds, abnormal wound healing, allergic rhinitis / sinusitis and asthma, inner ear disorders (specifically, hearing loss, tinnitus or vertigo), tenosynovitis, tendinitis, enthesitis or arthritis over a given time period. In one aspect of this embodiment, a suspension containing nanoparticles of clobetasol propionate reduces the frequency of side effects or complications associated with burn wounds, abnormal wound healing, allergic rhinitis / sinusitis and asthma, inner ear disorders (specifically, hearing loss, tinnitus, or vertigo), tenosynovitis, tendinitis, enthesitis, or arthritis by, for example, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% over a given period of time.

[0143] In another embodiment, a spray or droplets of a suspension of nanoparticles of clobetasol propionate are applied directly to areas of skin, eyes, nasal and sinus mucosa, intrapulmonary airways, or tympanic membrane affected by disease and / or injury. In the administration of the formulations of the present invention disclosed herein, the formulation itself is illustratively administered by dripping into the eyes or nose, or spraying onto the skin, eyes, nasal and sinus mucosa, inhalation into the lungs, or by application to the tympanic membrane, for example, using a spray or dropper or other suitable device. The spray bottle can be a pump-type spray bottle, a spray bottle, any form of inhaler, aerosol spray bottle, nebulizer bottle, metering device, etc.Droplets deliver a predetermined approximate volume of liquid (e.g., approximately 50 µL per application). The amount of formulation used is typically sufficient to cover the required surface area. In some embodiments, once the formulation is applied, a protective shield is placed on the formulation and left in place for an appropriate amount of time (e.g., 5 minutes, 10 minutes, 20 minutes, or longer; in some embodiments, one hour or two hours or longer). The protective shield can be simply a bandage, including bandages with a moisture-proof cover. For eye burns, the protective shield can simply be a bandage to protect external eye tissue and reduce the risk of mechanical damage or infection. For skin application, this essentially locks the formulation into contact with the skin and prevents the formulation from being deformed due to evaporation or distribution to other parts of the body or other people. The formulation can also be applied to the skin using standard application procedures, such as brushes, syringes, gauze pads, droppers, or any convenient applicator (e.g., for smaller areas). More complex application methods can also be used, including the use of delivery devices, but this is not necessary. External reservoirs for extended application of the formulation can also be employed.

[0144] In another embodiment, a suspension of clobetasol propionate nanoparticles is injected intratympanically or into the synovial space, tendon / ligament attachment point, or joint, or into a keloid or hypertrophic scar affected by disease and / or injury. In the administration of the formulation disclosed herein, the formulation itself is illustratively injected, for example, using a syringe and injection needle. The amount of formulation used is generally minimal and sufficient to treat the disease and / or injury. More complex administration methods may also be used, including the use of delivery devices, but this is not necessary. An external reservoir for extended administration of the formulation may also be employed. Without being bound by theory, it is thought herein that potent glucocorticoids (e.g., clobetasol propionate) reduce pathological scarring by reducing inflammation and fibroblast activation to limit the synthesis of scar tissue characteristic proteins (e.g., collagen), and ultimately lead to the regression of hypertrophic scars or keloids.

[0145] The formulation may be administered once, once a day, or more frequently as needed, for example, at a frequency of once daily to once hour (if desired). The formulations disclosed herein may be applied topically once or multiple times daily for periods of one to four weeks, one to two weeks, one week, two weeks, three weeks, four weeks, or four weeks or longer. In some cases, treatment may need to be continued indefinitely or as symptoms persist. Suitable applications of the formulation include, for example, once, twice, three times, four times, six times, eight times daily, or once every hour (if necessary). The formulations described herein may be injected once or multiple times daily for periods of one to four weeks, one to two weeks, one week, two weeks, three weeks, four weeks, or four weeks or longer.

[0146] The compositions according to the embodiments described herein have desired properties, such as desired solubility, viscosity, sprayability, spreadability, tonicity, injectability, syringe injectability, compatibility, homogeneity, resuspensionability, sterility, and stability.

[0147] In another embodiment, the pH of the formulation described herein is in the range of about 2 to about 8, or about 4.5 to about 6.5.

[0148] Examples It should be understood that the foregoing description and the following working examples are exemplary and illustrative, and are intended to provide a further understanding of the nature and scope of the invention described herein. It should be understood that the following non-limiting examples are a representative subset of the working embodiments of the invention and should not be considered as limiting any of the embodiments described herein, including those embodiments belonging to the type and amount of components of the formulation and / or its methods and uses.

[0149] Example 1. Preparation of a suspension formulation of clobetasol propionate nanoparticles The suspension formulation of clobetasol propionate nanoparticles was prepared by grinding clobetasol propionate drug particles with an abrasive as illustratively described in U.S. Patent Nos. 8,226,983, 10,588,913, and 11,376,262 and U.S. Patent Application Publication Nos. US 2018 / 0117064 and US 2020 / 0129526 to form a clobetasol propionate nanomixture. Subsequently, the nanomixture was dispersed in an aqueous medium using various excipients as illustratively described in Tables 1A, 1B, and 2.

[0150] Figure 1 shows a summary flowchart of the steps for generating the illustrative nanoparticle suspension of clobetasol propionate. Step A involves mixing the active pharmaceutical ingredient (API) with an abrasive. Illustrative abrasives include sodium chloride, hydrogenated soybean lecithin, and anhydrous citric acid. Step B involves grinding the compounded mixture with glycerol to produce a ground clobetasol propionate nanoparticle mixture with a particle size distribution D90 less than 250 nm.

[0151] Step C involves dispersing the clobetasol propionate nanoparticle mixture with poloxamer 407 and polyvinyl alcohol into a suspension using a high-shear homogenizer to prepare a nanoparticle suspension with a particle size distribution D90 less than 250 nm. In step D, the mixture is formulated and mixed with other excipients (including methylcellulose, preservatives (boric acid, EDTA, and benzalkonium chloride)), then the pH is adjusted with sodium citrate (e.g., trisodium citrate), the tension is adjusted with glycerol, and water for injection (WFI) is added to a sufficient volume. In step E, the formulated suspension undergoes final redispersion and is then aseptically filtered to produce a final aqueous suspension of clobetasol propionate nanoparticles.

[0152] The nano-grinding process produces a suspension of clobetasol propionate nanoparticles with an average particle size distribution in the range of approximately 120-200 nm. The nanoparticles are a milky white liquid, invisible to the naked eye, and feel smooth and comfortable when applied to the skin or mucous membranes. This suspension can be delivered as a sterile spray to large-area burn wounds or other mucous membranes, or as droplets to more limited areas of skin, eyes, nose, mucous membranes, or tympanic membranes, or as an injectable formulation into the tympanic cavity, keloids or scar tissue, synovial spaces, tendon / ligament attachment points, joints, or scars. Upon surface application or injection, the clobetasol propionate nanoparticles in the formulation effectively penetrate tissues to deliver therapeutically effective concentrations of clobetasol propionate to target tissues such as skin or eye burn wounds, nasal cavity, lungs, ear canal, inner ear, synovial spaces, tendon / ligament attachment points, joints, or scars. Aqueous sprays and droplets are advantageous for use with tissues that exudate fluids (e.g., burn wounds or inflamed nasal and sinus mucosa and respiratory airways).

[0153] Illustrative formulation compositions are shown in Tables 1A, 1B, and 2.

[0154] Table 1A - Illustrative composition of suspension formulation of clobetasol propionate nanoparticles 19 / 27 pages 22 CN 121038796 A

[0155] % is expressed as w / v (weight / volume), e.g., g / dL.

[0156] QS = sufficient Table 1B - Illustrative composition of suspension formulation of clobetasol propionate nanoparticles

[0157] % is expressed as w / v (weight / volume), e.g., g / dL.

[0158] QS = Sufficient quantity Table 2 - Illustrative composition of clobetasol propionate nanoparticle suspension formulation 20 / 27 pages 23 CN 121038796 A

[0159] % is expressed as w / v (weight / volume), for example g / dL.

[0160] qs = Sufficient quantity Example 2. Treatment of ocular burns The efficacy of clobetasol propionate nanosuspension 0.1% (CPN 0.1%) was evaluated in a New Zealand white rabbit (n=5 CPN 0.1% group; n=5 mediator group) ocular alkali burn model. Baseline slit-lamp ophthalmology, anterior optical coherence tomography (OCT) and corneal surface fluorescein staining were performed to confirm the absence of ocular abnormalities or damage. Ophthalmology was scored according to the modified McDonald-Shadduck Scoring System, and a score of zero for all parameters was required for inclusion in the study.

[0161] On day 1, animals were anesthetized with ketamine and toluenethiazide, and local anesthetics were applied to the study eye. To induce ocular alkali burns, a circular filter paper (No. 1 Whatman; about 5 mm in diameter) was soaked in 1 M NaOH for about 10 seconds and then placed in the center of the cornea of ​​the study eye for about 20 seconds.Immediately after removing the filter paper, the surface of the eye was rinsed with approximately 30 mL of balanced salt solution. Thirty minutes after the eye injury, the study eye was treated with one drop (approximately 50 µL) of CPN 0.1% or a mediator (n=5 CPN 0.1% group; n=5 mediator group). These treatments were continued four times daily (2 h apart) from day 1 to day 7 of the study. Antibiotic eye drops were applied to the study eye three times daily from day 1 to day 3 to prevent infection. Immediately after rinsing the alkali burn wound, on day 1, and on days 3 and 7 before administration, an ocular examination, slit-lamp photography, OCT measurements, and surface fluorescein staining were performed. Slit-lamp examination assessed corneal opacity, area of ​​corneal injury, corneal angiogenesis and conjunctival secretions, hyperemia, and swelling. Anterior OCT and fluorescein staining imaging were performed using the Spectralis® imaging platform and the Heidelberg retinal angiography-OCT device.

[0162] The results are shown in Figure 2. By day 3, compared to the mediator, CPN 0.1% treatment significantly and rapidly reduced clinical scores for inflammation, including conjunctival hyperemia and swelling, and corneal neovascularization (Student's unpaired t-test, p < 0.05) (Figure A). Compared to the mediator maintained until day 7, CPN 0.1% also rapidly reduced clinical scores for corneal opacity and stromal opacity by day 3 [two-way ANOVA, F (1, 8) = 12.25, p = 0.008] (Figure B). By day 7, surface fluorescein staining showed that CPN 0.1% treatment induced faster corneal epithelial healing compared to the mediator (Figure C). Figure C shows a representative image (a) of fluorescein staining for central corneal epithelial defects and a corresponding infrared image of the eye indicating the location of the pupil (central cornea) and iris (b). The size of the fluorescein stain defines the extent of corneal surface epithelial damage. By day 7, the CPN 0.1% group showed almost no fluorescein staining, while the mediator-treated eyes still exhibited significant fluorescein staining, indicating persistent corneal epithelial damage. By day 7, anterior OCT imaging showed a significant reduction in corneal thickness (edema) and corneal stromal opacity compared to the mediator group (Figure D). Figure D shows a representative cross-sectional OCT image of the damaged rabbit cornea on day 7 (the plane of the cross-section is indicated by the horizontal white line in the left image). The significantly reduced corneal thickness in the CPN 0.1% group (bottom image, arrow) indicates a significant reduction in corneal edema. The mediator group showed significantly more corneal thickness and opacity, indicated by the bright white area in the central cornea (top image, arrow).

[0163] Histological analysis confirmed that eyes treated with CPN 0.1% showed reduced incidence and severity of corneal stromal studies (fibrosis, mononuclear cell infiltration, edema, and neovascularization) and corneal epithelial hyperplasia / hypertrophy. CPN 0.1% rapidly and significantly reduced ocular inflammation, corneal opacity, and corneal stromal opacity, while also increasing the rate of corneal healing. The nanoparticle suspension formulation of clobetasol propionate described herein can be used for long-term improvement of visual acuity and visual sharpness after ocular alkali burns.

[0164] Example 3. Treatment of skin burn wounds The efficacy of CPN 0.1% in reducing inflammation and granulation tissue formation was evaluated in a pig burn wound model (n=3 female Yorkshire crossbred pigs, 35 ± 10 kg). On day 0, animals were first sedated with tiletamine-zolazepam and then anesthetized with isoflurane. Ten full-thickness burn wounds, each 2 cm in diameter, were created on the back of the animals using a 2 cm diameter brass rod (4.8 cm high, 100 g) heated to 100°C. To create the burn wounds, the rod was rapidly dried and placed on the skin surface for 45 seconds without applying additional pressure. The wounds were cleaned / excised with a 2 cm trephine saw, bandaged with a transparent film dressing (Tegaderm™), then with a blue absorbent pad, and finally wrapped with an elastic bandage. Postoperative pain was treated with buprenorphine (0.02 mg / kg, IM), and fentanyl patches (50 µg per hour) were applied to the shaved skin on days 0, 4, 7, and 11.

[0165] One animal's wound served as an untreated control wound, and wounds on both animals were treated with 0.1% CPN (i.e., n = 20 wounds CPN 0.1% group; n = 10 wounds untreated control group). CPN 0.1% treatment was initiated on day 0 after wound initiation, with additional treatments on days 2, 4, 7, and 9. On the treatment days, CPN 0.1% was applied to the wound surface via a sterile syringe and needle through the Tegaderm™ dressing at a volume of 1.5 mL on days 0–4 and 1 mL on days 7–9. On the treatment days, the wound was assessed using the modified Draize scoring system to evaluate erythema and edema. The extent of granulation tissue was assessed using a scoring system where a score of 1 indicates the absence of granulation tissue, a score of 2 indicates granulation tissue partially covering the wound floor, a score of 3 indicates granulation tissue completely covering the wound floor but not filling the wound volume, and a score of 4 indicates granulation tissue present throughout the entire wound volume.

[0166] The results are shown in Figure 3.CPN 0.1% reduced inflammation (erythema and edema) scores after only two treatments and significantly reduced granulation tissue volume from day 7 to day 11 (two-way ANOVA followed by Bonferroni's post-hoc test). Compared to control wounds, CPN 0.1% treatment rapidly reduced erythema (Figure A) and edema (Figure B) by day 4, with a significant reduction in edema by day 9, indicating accelerated wound healing. From day 7 to day 11, CPN 0.1% also reduced granulation tissue formation, demonstrating a reduction in hypertrophic scar formation (Figure C). In humans, up to 90% of burn wounds result in hypertrophic scarring, and extensive and prolonged inflammation and excessive granulation tissue formation are considered key drivers of hypertrophic scar formation. The nanoparticle suspension formulation of clobetasol propionate described in this article can be used to reduce hypertrophic scar formation in burn wounds.

[0167] Example 4. Treatment and Reduction of Hypertrophic Scarring The efficacy of CPN 0.1% in reducing hypertrophic scarring was evaluated in a rabbit ear hypertrophic scar model (n=2 New Zealand White rabbits, 2.5-3 kg). One rabbit was treated with CPN 0.1% (n=8 wounds), and another rabbit served as an untreated control (n=8 wounds). On day 0, animals were anesthetized with ketamine / toluidine, and four full-thickness excision wounds with a diameter of 7 mm were surgically created on the ventral side of both ears of each rabbit. CPN 0.1% treatment was initiated once daily for 60 minutes after wound creation and continued for 3 weeks, 5 days a week. The treatment consisted of applying 50 µL of CPN 0.1% to the wound, covering it with a piece of 8×8 mm sterile filter paper, and then applying another 50 µL of CPN 0.1% to the filter paper. The wound was bandaged with a circular Band-Aid adhesive dressing, followed by a transparent film dressing (Tegaderm™). Untreated control wounds were bandaged in the exact same manner, except that no treatment was applied. Twice weekly, the wound was assessed for inflammation using the Dreiz scoring system, where erythema scores were 0 for no erythema, 1 for mild erythema, 2 for well-defined erythema, 3 for moderate to severe erythema, and 4 for severe erythema or eschar. Edema scores were 0 for no edema, 1 for mild edema, 2 for mild edema with well-defined borders, 3 for edema (elevation >1 mm), and 4 for severe edema (elevation >1 mm and extending beyond the treatment site). On day 28 (7 days after the last treatment), animals were euthanized and the wound was collected, fixed, and stained with Masson's trichrome for histological evaluation.

[0168] The results are shown in Figure 4.During the first week of treatment, CPN 0.1% rapidly and significantly reduced erythema [two-way ANOVA, F(8, 112) = 3.695, p = 0.0007] and edema [two-way ANOVA, F(8, 112) = 4.680, p < 0.0001] compared to the control. On day 28, histological analysis showed hypertrophic scarring in all wounds in the untreated control group, indicated by increased scar formation. CPN 0.1% treatment significantly reduced new collagen formation (Fig. A), scar height (Fig. B), and scar area (Fig. C) compared to the control (Student's unpaired t-test). Fig. D shows representative images of untreated wounds and wounds treated with CPN 0.1% on day 28. Overall scar size was determined by measuring the pixel area of ​​the scar, and scar height was determined by the pixel height of the scar from the base of the wound to the top of the epithelium. Scar height was measured at the arrow. There was clear evidence of hypertrophic scarring in the untreated control wound (top image, shaded box) and a lack of hypertrophic scarring in the wound treated with 0.1% CPN (bottom image). The nanoparticle suspension formulation of clobetasol propionate described herein significantly and substantially reduced and / or prevented abnormal hypertrophic scarring in the wound.

[0169] Example 5. Reduction or removal of abnormal hypertrophic scarring The efficacy of intralesional injection of the nanoparticle suspension formulation of clobetasol propionate described herein in reducing hypertrophic scarring was evaluated in a rabbit ear hypertrophic scar model. For example, on day 0, New Zealand white rabbits were anesthetized with ketamine / toluidine (n=4 CPN 0.1% group; n=4 mediator group) and four full-thickness excision wounds with a diameter of 7 mm were surgically created on the ventral side of both ears. The wounds remained untreated for 20 days, at which time the wounds closed and developed hypertrophic raised scars. On days 21, 28, and 35, 0.1% CPN or the medium (10 µL) was injected into the scar using a 32-gauge needle and a microsyringe pump (Hamilton). On day 40, the animals were euthanized and the wound was excised, fixed, and stained with Mason chromatogram for histological evaluation of collagen and fibroblast structures.

[0170] Histological analysis was used to compare hypertrophic scarring in the wound, indicated by increased scar formation and disordered collagen and fibroblast structures. Intralesional injection of the suspension of clobetasol propionate nanoparticles described herein was expected to significantly reduce new collagen formation, scar height, abnormal fibroblast structures, and scar area compared to the control, resulting in the absence of hypertrophic scarring, suggesting that intralesional injection of the suspension of clobetasol propionate nanoparticles described herein could significantly reduce the size of abnormal hypertrophic scars in the wound.

[0171] Example 6. Treatment of tenosynovitis, tendinitis, enthesitis and arthritis: Evaluation of the efficacy of CPN 0.1% in reducing arthritis symptoms in a rat collagen-induced arthritis (CIA) model.To induce the arthritis phenotype, on day 0, male Lewis rats (n=20, 200–250 g) were subcutaneously injected with 200 µL of 1 mg / mL bovine type II collagen / incomplete Freund's adjuvant solution at the base of the tail, followed by a booster injection of 100 µL on day 7. By days 28–42, the CIA model had developed an arthritis phenotype in one or both hind limbs of the rats, resulting in paw swelling and inflammation of the joints and tendons. Once the arthritis phenotype was developed (see instructions on page 23 / 27, CN 121038796 A), 0.1% CPN or the mediator (50 µL) was subcutaneously injected once daily into the paw pads of both hind paws for 14 days (randomized to n=10 CPN 0.1% group; n=10 mediator group). Inflammation in the hind paws was assessed daily using a clinical score of 0–4, where 0 was normal, 1 indicated mild redness and swelling of the ankle or toes, 2 indicated moderate redness and swelling of the ankle and paws, 3 indicated severe redness and swelling of the entire ankle and paws, including the toes, and 4 indicated maximum inflammation of the hind limbs involving multiple joints. Paw volume was measured twice weekly using organ fill measurement. On day 15, the paw and joint inflammation of the rats was assessed, followed by euthanasia.

[0172] The results are shown in Figure 5. Compared to the mediator, CPN 0.1% rapidly and significantly reduced clinical scores for hind paw inflammation (Figure A) and hind paw volume (Figure B) by day 3 of treatment (two-way ANOVA followed by Bonferroni post-hoc test). These effects were maintained throughout the observation period. Rats treated with 0.1% CPN had paws that appeared normal for 7 days after treatment, while animals treated with the mediator showed decreased mobility due to inflammation of the paws, joints, and tendons throughout the observation period. 0.1% CPN rapidly and significantly reduced paw swelling and joint and tendon inflammation, indicating that the suspension formulation of clobetasol propionate nanoparticles described herein can be used to reduce inflammation around the joints, tendons, and ligaments in subjects with arthritis, tenosynovitis, tendinitis, and enthesitis.

[0173] Example 7. Treatment of Inner Ear Disorders (Hearing Loss) The efficacy of the suspension formulation of clobetasol propionate nanoparticles described herein was evaluated in a noise-induced hearing loss model. For example, C57BL / 6J mice (n=10 CPN 0.1% group; n=10 mediator group) were housed in a noise-controlled environment throughout the study. Baseline hearing thresholds were measured using bilateral auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) at 5–40 kHz. On day 0, animals were anesthetized with isoflurane and received an intratympanic injection of 5 µL of 0.1% CPN or a mediator (IT) into the ear.IT injections were administered to animals fixed in a stereotactic device equipped with a micro-syringe / micro-infusion pump assembly. Following the IT injection, the animals were held in place with the injected ear facing upwards for 30 minutes to allow the drug suspension to contact the round window membrane and for clobetasol propionate to diffuse into the inner ear fluid.

[0174] 1.5 h after the IT injection, the animals underwent a single noise exposure in a soundproof chamber. Mice were exposed to noise in wire cages surrounded by ceramic speakers, with noise generated and filtered to 4.0–45.0 kHz. Mice were exposed to 110 dB once for 30 minutes. Two weeks after the noise exposure, ABR hearing threshold assessments were performed, followed by euthanasia and cochlear harvesting for histological analysis of the auditory apparatus of the inner ear.

[0175] The histological analysis of the cochlea was used to compare the internal and external hair cell counts and the degree of preservation of neural connections between the treatment group and the mediator treatment group. It is expected that IT administration of the formulation described herein will show significantly less ABR threshold shift, indicating that the formulation prevents noise-induced hearing loss compared to mediator injection, suggesting that the suspension formulation of clobetasol propionate nanoparticles can be used to treat noise-induced hearing loss by reducing cochlear hair cell loss and preserving hearing.

[0176] Example 8. Treatment of Inner Ear Disorder (Tinnitus) The efficacy of IT injection of the suspension formulation of clobetasol propionate nanoparticles described herein in reducing tinnitus was evaluated in a mouse model. For example, C57BL / 6J mice (n=10 CPN 0.1% group; n=10 mediator group) were tested using a sound-based avoidance detection (SBAD) paradigm. Mice were trained in a shuttle box to perform Go or No-Go operation responses using foot shocks (0.1–0.4 mA) as negative reinforcement. The shuttle box had two identical chambers with a louvered door in the middle, and beams were present throughout the shuttle box to detect the animal's position. The Go test monitors motor, motivational, and learning / memory functions, while the No-Go test monitors tinnitus-like behaviors. Both types of tests are consistently randomly assigned during each training and testing phase, with a 4-second interval between tests. The training phase begins with a 2-minute adaptation period, followed by 100 tests per day for a total of 30–40 minutes. In the Go test, animals are trained to move from one compartment to another as soon as any sound stimulus is presented. When they move to the other compartment, the blinds are closed. If they do not move through the blinds, they receive a 5-second foot shock after the sound stimulus begins (see page 27 of the instruction manual, CN 121038796 A). In the No-Go test, animals are trained to remain in the compartment if no sound is presented. If they pass through the blinds within 10 seconds, they receive a shock, but the blinds remain open. For both the Go and No-Go tests, the shocks are turned off after the animal moves to another compartment or at the end of the test.The sound stimuli were presented randomly and varied in both frequency and intensity.

[0177] During testing, foot shocks continued to be applied after an error occurred in the Go test, and the blinds were closed once the animal moved to another compartment. However, in the No-Go test, shocks were no longer applied and the blinds were closed immediately if the animal entered another compartment. Therefore, in the No-Go test, moving from one compartment to another in the absence of external sound stimulation indicates that the animal has tinnitus.

[0178] After successfully completing SBAD training (90-100% correct test response), mice were subjected to unilateral noise-induced trauma, resulting in tinnitus. On day 0 before noise exposure, mice were anesthetized with isoflurane and received an injection of 0.1% CPN or the mediator IT (5 µL) into the right ear. The IT injection was administered to animals fixed in a stereotactic device equipped with a microsyringe / microinfusion pump assembly. Following IT injection, the animals were held in place with the injected ear facing upwards for 30 minutes to allow the drug suspension to contact the round window membrane and allow clobetasol propionate to diffuse into the inner ear fluid. The left ear was plugged with a modified earplug (Decidamp2™) and secured in place with Stomahesive™ (ConvaTec). Two hours later, the mice were placed in a sound-attenuated chamber and exposed to 120 dB broadband noise (4–25 kHz) for 2 h.

[0179] To assess the presence of tinnitus, mice underwent the SBAD test at 2 weeks, 1 month, and 2 months after noise exposure. At each time point, the mediator group and the treatment group showed almost no errors in the Go test, indicating normal motivation, motor, and memory / learning functions. However, in the No-Go test, the mediator group showed a larger percentage of errors compared to the treatment group, i.e., mice moving from one compartment to another in the absence of external sound stimulation, indicating the presence of tinnitus. Efficacy was confirmed when the correct response rate (i.e., not moving from one compartment to another in the absence of external sound stimulation) in the No-Go test was 20% or higher. A low error rate (90-100% correct response) in the No-Go test indicates high efficacy in reducing noise-induced tinnitus. It is expected that the IT injection of the suspension formulation of clobetasol propionate nanoparticles described herein will show a high percentage of correct responses, indicating that the formulation may be used to treat tinnitus in subjects, including humans.

[0180] Example 9. Treatment of Allergic Rhinitis / Sinusitis The suspension formulation of clobetasol propionate nanoparticles described herein may be used to treat subjects suffering from allergic rhinitis. For example, a 30-year-old woman visited a clinic complaining of excessive nasal discharge, nasal itching, and difficulty breathing through her nose, which could not be improved with conventional allergy treatments. The clinician observed the following characteristic signs / symptoms of allergic rhinitis: nasal exudate, deep redness of the nasal mucosa, and significant swelling of the nasal and sinus mucosa.Clinicians recognized that conventional allergy treatments might not be effective in treating the symptoms and signs of subjects, especially when significant fluid exudate was present. In this example, clinicians used a spray bottle to apply an aqueous suspension of clobetasol propionate nanoparticles to the nasal and sinus mucosa. The liquid suspension was applied as evenly as possible to the entire mucosal surface of the nose by spraying and allowed to stand for five to ten minutes. Thereafter, the liquid suspension was reapplied once daily or more frequently for a period of one week or longer. After one week or longer, the subject returned to the clinic for evaluation. The subject reported a significant improvement in the symptoms and signs of allergic rhinitis and reported to the clinician that the treatment reduced itching and difficulty breathing through the nose. Further observation by the clinician confirmed that the use of the clobetasol propionate nanoparticle suspension resulted in faster resolution of rhinitis. The clobetasol propionate nanoparticle suspension demonstrated that the treatment of allergic rhinitis was effective, convenient, and comfortable.

[0181] Example 10. Treatment of Asthma The clobetasol propionate nanoparticle suspension formulation described herein can be used to treat subjects with asthma. For example, a 15-year-old female visited a clinic complaining of shortness of breath, chest tightness and pain, wheezing and coughing. The clinician recognized these symptoms as consistent with asthma and administered standard treatment to quickly relieve acute asthma symptoms. In this example, the clinician demonstrated to the subject how to use an inhaler to administer an aqueous suspension of clobetasol propionate nanoparticles described herein to treat asthma. The liquid suspension was inhaled into the lungs once or more daily to treat asthma symptoms. After a week or longer, the subject returned to the clinic for evaluation. The subject acknowledged significant improvement in asthma symptoms and currently had free breathing without asthma symptoms. Further observation by the clinician confirmed that clobetasol propionate was effective in treating asthma. This demonstrates that the suspension of clobetasol propionate nanoparticles is effective, convenient and comfortable in treating asthma.

[0182] Example 11. Effect of methylcellulose concentration on tissue penetration The tissue penetration of the clobetasol propionate nanoparticle suspension formulation into the conjunctiva was measured using a standard protocol.

[0183] Table 3. Concentration of clobetasol propionate in ocular tissue after one drop (50 µL) of the suspension formulation of clobetasol propionate nanoparticles was instilled into a rabbit eye.

[0184] Cmax (ng / g) = Peak concentration (ng / g tissue) *The composition includes all other excipients at the same levels listed in Table 2 for CPN 0.05%, except for methylcellulose.

[0185] The suspension of clobetasol propionate nanoparticles described herein provides a longer half-life after topical application to the ocular surface (i.e., the active ingredient clobetasol propionate retains its pharmacological activity in target tissues such as the conjunctiva).In addition, the suspension of clobetasol propionate nanoparticles described herein provides a higher concentration (Cmax) and therapeutic exposure of clobetasol propionate in the target tissue at an equivalent dose of the active ingredient in the formulation.

[0186] Example 11. Effect of boric acid and EDTA on tissue permeability The tissue permeation of the suspension of clobetasol propionate nanoparticles to the cornea was measured using a standard protocol. After applying one drop (50 µL) of the 0.05% clobetasol propionate nanoparticle formulation shown in Table 2 to the topical ocular surface, the concentration of clobetasol propionate in the target tissue was measured for pharmacological activity following application of the formulation containing boric acid and disodium edetate (EDTA) described herein (Table 4).

[0187] Table 4. Concentration of clobetasol propionate in the cornea after one drop (50 µL) of the suspension formulation of clobetasol propionate nanoparticles was instilled into a rabbit eye

[0188] Cmax (ng / g) = peak concentration (ng / g tissue) *The composition includes all other excipients listed in Table 2 at the same level for CPN 0.1%, except that it does not contain boric acid and EDTA.

[0189] The suspension of clobetasol propionate nanoparticles containing boric acid and EDTA described herein provides higher concentrations and therapeutic exposure of clobetasol propionate in target tissues such as the cornea at equivalent doses of the active ingredient, as described in the specification on pages 26 / 27 of CN 121038796 A. Different doses of 0.05% and 0.1% were normalized when Cmax values ​​were presented.

[0190] To further describe the invention, all patents, patent publications and other publications referenced and identified in this specification are individually and explicitly incorporated herein by reference in their entirety. However, the referenced patents, patent publications and other publications should not be construed as accepted prior art. Instruction manual, page 27 / 27, 30 CN 121038796 A, Figure 1; Instruction manual, Figure 1 / 8, page 31 CN 121038796 A, Figure 2; Instruction manual, Figure 2 / 8, page 32 CN 121038796 A, Figure 2 (continued); Instruction manual, Figure 3 / 8, page 33 CN 121038796 A, Figure 3; Instruction manual, Figure 4 / 8, page 34 CN 121038796 A, Figure 3 (continued); Instruction manual, Figure 5 / 8, page 35 CN 121038796 A, Figure 4; Instruction manual, Figure 6 / 8, page 36 CN 121038796 A, Figure 4 (continued); Instruction manual, Figure 7 / 8, page 37 CN 121038796 A, Figure 5; Instruction manual, Figure 8 / 8, page 38 CN 121038796 A.

Claims

1. A method for treating skin or eye burns in a subject, the method comprising applying a sterile suspension of clobetasol propionate nanoparticles to the burn site.

2. A method for treating a subject with abnormal wound healing, hypertrophic scarring, or keloids, the method comprising contacting the patient’s skin wound, scar, or keloid with a sterile suspension of clobetasol propionate nanoparticles.

3. A method for treating a subject suffering from allergic rhinitis / sinusitis or asthma, the method comprising contacting the patient’s nasal and sinus mucosa or airway with a suspension of clobetasol propionate nanoparticles.

4. A method for treating a subject suffering from an inner ear disorder, specifically hearing loss, tinnitus, or vertigo, the method comprising contacting a suspension of clobetasol propionate nanoparticles with a tympanic membrane or delivering a suspension of clobetasol propionate nanoparticles to the patient's inner ear or nasal mucosa.

5. A method for treating a subject suffering from tenosynovitis, tendinitis, or enthesitis, the method comprising injecting a sterile suspension of clobetasol propionate nanoparticles into the synovial space or tendon / ligament enthesium of the patient.

6. A method for treating a subject suffering from arthritis, the method comprising injecting a sterile suspension of clobetasol propionate nanoparticles into the joint of the patient.

7. The method of claims 1, 2, 3 and 4, wherein a spray bottle, dropper bottle or aerosol device is used, or the suspension formulation of the clobetasol propionate nanoparticles is applied by injection with a syringe and injection needle.

8. The method of claims 5 and 6, wherein the sterile suspension of clobetasol propionate nanoparticles is injected using a syringe and injection needle.

9. The method of claims 1 and 2, wherein the suspension formulation of clobetasol propionate nanoparticles reduces complications of burns or abnormal wound healing, including inflammation, pain, abnormal granulation, scarring, contracture, deformity, pigmentation, or visual impairment.

10. The method of claims 3 to 6, wherein the suspension formulation of clobetasol propionate nanoparticles reduces complications of allergic rhinitis / sinusitis, asthma, inner ear disorders, tenosynovitis, tendinitis, enthesitis, or arthritis.

11. The method of claim 4, wherein the suspension formulation of clobetasol propionate nanoparticles reduces complications of inner ear disorders, including tinnitus, vertigo, and hearing loss.

12. The method of claims 5 and 6, wherein the suspension formulation of clobetasol propionate nanoparticles reduces complications of tenosynovitis, tendinitis, enthesitis, or arthritis, including pain and / or discomfort or decreased mobility.

13. The method of any one of claims 1 to 6, wherein the suspension formulation of clobetasol propionate nanoparticles reduces inflammation.

14. The method of claims 5 and 6, wherein the suspension formulation of clobetasol propionate nanoparticles improves joint, tendon, or ligament function.

15. The method of any one of claims 1 to 14, wherein a suspension of the nanoparticles of clobetasol propionate is applied once or more daily to the burned skin or eyes, nose, respiratory tract, nasal mucosa, tympanic membrane, inner ear, synovial space, ligament or joint for up to 52 weeks.

16. A droplet, spray, mist, aerosol, or injectable formulation comprising clobetasol propionate, wherein the clobetasol propionate is formulated as a suspension of nanoparticles.

17. The droplet, spray, mist, aerosol, or injectable formulation of claim 16, further comprising sodium chloride, hydrogenated soybean, lecithin, anhydrous citric acid, glycerol, poloxamer 407, polyvinyl alcohol (PVA), boric acid, disodium edetate dihydrate, benzalkonium chloride, methylcellulose, or trisodium citrate, or combinations thereof.

18. The droplet, spray, mist, aerosol, or injectable formulation as described in claim 16, wherein it is in a sterile form.

19. The droplet, mist, spray, or aerosol or injectable formulation of claim 16, further comprising an antioxidant, an antimicrobial agent, an anti-inflammatory agent, an anesthetic, an analgesic, a lubricant, a flavoring agent, or a combination thereof.

20. A unit dose configured for administration by injection or eye drops, said unit dose comprising clobetasol propionate, wherein said clobetasol propionate is formulated as a sterile suspension of nanoparticles.

21. The unit dose as described in claim 20, further comprising sodium chloride, hydrogenated soybean, lecithin, anhydrous citric acid, glycerol, poloxamer 407, polyvinyl alcohol (PVA), boric acid, disodium edetate dihydrate, benzalkonium chloride, methylcellulose, or trisodium citrate, or combinations thereof.

22. The unit dose as claimed in claim 20, further comprising an antioxidant, an antimicrobial agent, an anesthetic, an analgesic, or a combination thereof.

23. The method of claim 2, wherein the spray or droplets of claim 16 are applied to the surface of the subject's skin or eyes.

24. The method of claim 2, wherein the injection as described in claim 16 is injected into the hypertrophic scar or keloid of the subject.

25. The method of claim 3, wherein the spray or droplets of claim 16 are applied to the nasal and sinus mucosa of the subject.

26. The method of claim 3, wherein the spray or droplets of claim 16 are inhaled into the lungs.

27. The method of claim 4, wherein the spray or droplets of claim 16 are applied to the tympanic membrane of the ear or to the nasal mucosa.

28. The method of claim 4, wherein the unit dose of claim 20 is administered via intratympanic injection.

29. The method of claim 5, wherein the unit dose as described in claim 20 is injected into the synovial space or tendon / ligament attachment point of the subject.

30. The method of claim 6, wherein the unit dose as described in claim 20 is injected into the joint of the subject.

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