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

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

[0002] Treatment of burns Burns are injuries to the skin or other tissues (including tissues in the eyes) caused by a variety of factors, damaging cellular structure. The severity of burns varies depending on the extent of tissue damage, sometimes resulting in widespread tissue inflammation, cell death, and necrosis. Treatment for 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] Eye burns are particularly problematic because the damage can cause irreversible harm to the cornea and other structures in the eye, significantly impacting vision. The cornea is the primary refractive tissue at 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 makes up about 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 stroma, a highly ordered structure containing several types of collagen fibers and other extracellular matrix molecules. When this complex stroma is disrupted 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 post-burn inflammation, edema, neovascularization, and structural disruption of the stroma's proteins. Current treatments cannot completely and effectively restore 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 cases 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. Normally, 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 effectiveness. Injections of conventional steroid preparations are limited because this suboptimal treatment requires repeated painful injections, but these 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 triggered 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, requiring intervention to prevent serious complications such as airway narrowing. There is a continued need for therapeutic agents and methods for treating 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 triggers the release of inflammatory mediators, causing bronchospasm, airway edema, and abnormal mucus production, leading to the characteristic asthma symptoms. In some cases, conventional steroid preparations can be used, but they generally must be co-administered with a beta-adrenergic receptor agonist 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 beta-agonists. Therefore, there is a persistent need for therapeutic agents and methods for treating 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 known as Ménière's disease. These inner ear disorders are often accompanied by endolymphatic hydrops, which is the expansion of the endolymphatic compartments in 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, limited, or have 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 inflammation of the tendon within the synovial sheath, while enthesitis is inflammation of the tendon or ligament that attaches to the bone. As tendons move within their sheaths or at their attachment points to bone, they can be irritated by trauma or repetitive or excessive movement, causing inflammation, pain, and potentially severe functional limitations. Chronic inflammation can lead to swelling and / or fibrosis within the tendon sheath, reducing space for the tendon and causing conditions such as trigger finger or nerve compression, as seen in carpal tunnel syndrome. Repetitive joint movements or impacts from vibrating tools can trigger inflammatory processes in the tendon sheath or attachment points, which can occur in the hands or feet and affect individuals in many occupational types.

[0010] Medical treatment for tenosynovitis, tendinitis, and enthesitis includes using splints to reduce tendon movement and corticosteroid injections. In some cases, when pain and impaired tendon function do not respond to rest and anti-inflammatory treatment, surgery is required, 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, and although it can occur at any age after 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 loss of 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 deformities.

[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, the 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 total joint replacement to preserve joint function and movement, remains the only option in some severe cases of arthritis. Therefore, there is a continued 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] This article has found 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, this document describes compositions of nanosuspensions containing glucocorticoids 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, this document describes a method for treating skin or eye burns, abnormal wound healing, allergic rhinitis / sinusitis, asthma, and inner ear disorders. The method comprises administering an effective amount of a glucocorticoid nanosuspension to a subject in need.

[0017] In another embodiment, this document describes the use of a composition comprising a nanosuspension of a glucocorticoid 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.

[0018] In another embodiment, this document describes packaging articles and kits comprising compositions containing nanosuspensions of glucocorticoids. The packaging articles and kits include instructions for using the nanosuspensions 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 various 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 present invention include 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 present 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 invention include application of a spray, mist, aerosol, or droplet into the nasal cavity to treat allergic rhinitis / sinusitis or inhalation 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 the application of a spray or droplet to the tympanic membrane via 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 argues 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 potent 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 arthritis.

[0024] In another illustrative embodiment, this document describes a suspension formulation in the form of a spray, mist, aerosol, injectable, or droplet 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, this document describes a method for manufacturing nanoparticle suspensions of corticosteroids and / or glucocorticoids (e.g., clobetasol propionate).

[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. Attached Figure Description

[0028] Figure 1 A flowchart is shown showing the steps for producing an illustrative suspension formulation of clobetasol propionate nanoparticles.

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

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

[0031] Figure 4 A-4D demonstrates the efficacy of CPN at 0.1% in a rabbit ear hypertrophic scar model. Statistical difference compared to the untreated control is indicated by * (p<0.05).

[0032] Figure 5 A-5B demonstrates the efficacy of 0.1% CPN in a male Lewis rat model of collagen-induced arthritis (CIA). Statistical differences compared to the mediator are indicated by * (p<0.05). Detailed Implementation

[0033] The following illustrative clauses set forth other 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 disorder (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 disorder), airway and lung tissue, or tympanic membrane of the ear.

[0034] 2. The method of Clause 1, wherein the 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 the 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 the clobetasol propionate nanoparticles improves wound healing, relieves allergic rhinitis / sinusitis or asthma, or reduces hearing loss, tinnitus or dizziness.

[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 enthesus, 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 subject's tympanic cavity, synovial space, tendon attachment point, or joint, 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 formulation is introduced by injection, for example by using a syringe and injection needle.

[0043] 11. The method as described in Clause 8 or 9, wherein the inner ear disorder is caused by noise, trauma, or ototoxic chemicals.

[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 the nanoparticles of clobetasol propionate 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 the nanoparticles of said clobetasol propionate reduces hearing, tinnitus, dizziness, or improves joint or tendon function.

[0048] 16. The method of any of the preceding clauses, wherein the suspension formulation of the 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, or aerosols or injectable formulations 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 as described in any of Clauses 17 to 19 and / or any of the methods used in Clauses 1 to 16, which further contain 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 as in Clause 21, used in any of the methods described in Clauses 1 to 16.

[0055] 23. The unit dose of any of the methods used in Clauses 21 or 22 and / or Clauses 1 to 15 further comprises 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] definition The term "implementation" generally refers to an illustrative example 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 specific 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 are not necessarily included in the invention.

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

[0058] The use of any instance (including instances of any terminology discussed herein) anywhere in this specification is merely illustrative and is not intended to further limit the scope and meaning of this disclosure or any exemplary terminology. 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” generally refer to a substance, compound, chemical, or molecule that has biological activity or otherwise induces biological, physiological, or pharmacological effects in a subject to which it is administered. In other words, an “active agent” or “active ingredient” refers to one or more components of a composition attributable to all or part of the composition’s effects. Glucocorticoids may be the primary active agent, or in other words, the component of the composition attributable to all or part of the composition’s effects. An active agent may be a secondary agent, or in other words, a component of the composition 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. This outcome may be a reduction or improvement of the signs, symptoms, or cause of a disease, or any other desired change in a biological system. When the desired outcome is a therapeutic response, it should be understood that the effective amount will vary depending on: 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 rate of excretion; 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 a person skilled in the art.

[0061] The terms “treating” or “alleviation” generally refer to both therapeutic treatment and preventative or preventative measures, the purpose of which 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, the subject is successfully “treated” for the disease, condition, or disease. For example, for 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 reducing scar tissue size, a faster healing process, and / or improved healing; for eye burns, treatment or prevention may include reducing corneal opacity and improving vision; for allergic rhinitis / sinusitis, treatment or prevention may include reducing nasal discharge and symptoms such as itching and nasal congestion; for asthma, treatment or prevention may include reducing bronchoconstriction, wheezing, shortness of breath, chest tightness, pain, or cough; for inner ear disorders, treatment or prevention may include improving hearing, vertigo, and tinnitus; and for tenosynovitis, tendinitis, enthesitis, and arthritis, treatment or prevention may include reducing pain, swelling, and deformity, and improving mobility.

[0062] The term "application" generally refers to the introduction of a predetermined amount of a substance into or onto a subject by a 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 following: type, severity and location of burn wounds, abnormal wound healing, allergic rhinitis / sinusitis, asthma, inner ear disorders (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 syndrome" generally refer to a wide range of conditions, 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, exposure to chemicals, 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 syndromes, despite their different origins, share common symptoms and disease progression.

[0065] The term "allergic rhinitis / sinusitis" generally refers to a range of conditions, including those caused by seasonal exposure to allergens (such as 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 symptoms, 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 / physical activity.

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

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

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

[0070] The term "arthritis" generally refers to a range of conditions, including those caused by both infectious and non-infectious factors. Non-infectious factors 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 tiny blood vessels that form in a wound during the healing process. Granulation tissue typically grows from the sides and base of the wound and can fill 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 fibroblast proliferation and new, thin-walled, delicate capillaries (angiogenesis) within a loose extracellular matrix of proteins (such as collagen), along with infiltrating inflammatory cells.

[0073] The term "corneal opacity" is generally used to describe a condition where corneal opacity or scarring leads to a loss of corneal transparency, 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 fibers in the cornea and the absence of edema. Changes in the spacing and type of collagen fibers, as well as edema, can 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 mechanisms of the immune system, reducing certain aspects of immune function, such as inflammation. Therefore, they are commonly used to treat diseases caused by an overactive immune system (such as allergies, asthma, steroid-sensitive skin diseases, and autoimmune diseases). Clobetasol propionate is a highly selective and potent glucocorticoid receptor agonist.

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

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

[0077] The term "nanoparticle" generally refers to small particles with an average particle size typically ranging from 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 as aqueous suspensions. 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 drug particle diameter to increase over time and resulting in a loss of homogeneity in the suspension contents. Due to these problems, it is difficult to achieve uniform dispersion of larger particles and consistent application of the active ingredient. Furthermore, 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 present these aggregation or clumping problems.

[0079] As used herein, the particle size distribution of suspended nanoparticles in the formulation was determined using dynamic light scattering with a commercially available instrument such as the Otsuka ELSZ-2000ZS particle size analyzer. This analyzer generates a histogram of the particle size distribution, from which D is determined. 10 D 50D 90 and average particle size.

[0080] The term "metered-dose spray" or "MDTS" generally refers to a device that delivers medication to the surface of the skin, mucous membranes, or airways for sustained absorption into the tissues. It works in a manner similar to percutaneous patches or topical gels. The medication 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 where skin or other tissue has been injured, such as by burns or other trauma. Scarring is 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 deposits of connective tissue and collagen occur within 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 much larger than the original wound area. These types of scars can cause severe, permanent cosmetic damage.

[0082] The term "contraction" generally refers to an abnormal event that occurs when a large area of ​​skin is damaged or lost, resulting in scarring. Scar formation pulls the edges of the skin 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 points, or joints. Treatment options for contracture release include surgery, where 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 of the tissue.

[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 integers 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 integers from 0 to 8 also describes each subrange, each of which can be the basis for another implementation, such as n being integers 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 series of values ​​that, after proper rounding, will match that number. For instance, it should be understood that stating the number 1 with a single significant figure appropriately refers to a series 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 series 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 lower precision.

[0085] As used herein, the term “approximately” when used with numerical values ​​or limits generally means 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 approximately 5 will include at least the range 4.5 to 5.4, since each of those values ​​is rounded to 5. Similarly, for a real number expressed with additional significant figures, the corresponding rounding range applies to the last significant figure. Integers will include at least the values ​​±1 (for single-digit numbers), ±10 (for two-digit numbers), etc. Depending on the context and variables, the term “approximately” is also interpreted to consider a range based on a percentage of the stated number; for example, approximately 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. Furthermore, depending on the context, unless otherwise indicated, a stated number should not be interpreted to include a zero value 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 field.

[0087] Unless otherwise indicated, the percentage (%) of ingredients and components in the formulations described herein, expressed as % w / v, refers 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 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 subsequent additional active pharmaceutical ingredients are for treating conditions and / or symptoms distinct 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. Illustrative additional active pharmaceutical ingredients may include, for example, active ingredients for treating pain, accompanying bacterial infections, cough, congestion, etc.

[0089] In an implementation that includes a list of alternatives that may be included individually or in various combinations, it should be understood that the list also describes each individual alternative and a list of all possible subsets of those alternatives.

[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" refers to 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 refer to or 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 formulations on damaged skin tissue can cause pain and problems. More severe tissue damage (e.g., 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 are 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] While some glucocorticoids are already used to treat allergic rhinitis / sinusitis and asthma, this article argues that the formulations described herein and / or the use of glucocorticoids such as clobetasol propionate 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, smaller injection volumes have the potential benefit of reducing post-injection pain. Additionally, when conventional formulations are insufficient to improve symptoms, the formulations described herein using glucocorticoids with threshold activity levels (e.g., clobetasol propionate) can be administered directly to the tympanic membrane or tympanic cavity via the external auditory canal as a spray or ear drops, or applied to 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, the nasal cavity, 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, suspension formulations of clobetasol propionate nanoparticles are 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 covers a large surface area and avoids the pain associated with mechanical application required to rub conventional ointments / lotions onto burns, thus providing efficiency and comfort. The nanoparticle suspensions allow clobetasol propionate to penetrate effectively into burn tissue, thus exhibiting improved clinical efficacy and safety characteristics compared to conventional formulations.

[0095] Certain suspension formulations described in this article are optimized for the treatment of abnormal wound healing and can be applied by spraying or dripping onto the abnormally healing wound or by injection into the wound. The nanoparticle suspensions allow clobetasol propionate to penetrate effectively into tissues, thus exhibiting superior clinical efficacy and tolerability 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. These formulations can be applied via spray, aerosol, or droplets to the nasal and sinus mucosa, inhaled into the lungs, applied to the tympanic membrane through the external auditory canal, or injected into the tympanic cavity, synovial space, enthesium, or intra-articular region. The nanoparticle suspensions allow clobetasol propionate to penetrate effectively into tissues, thus exhibiting superior clinical efficacy and tolerability compared to conventional formulations.

[0097] Nanoparticle suspension formulations can be produced by dispersing nano-milled clobetasol propionate, optionally with a mixture of one or more excipients, in an aqueous formulation. The nanomilling method allows clobetasol propionate to be formulated into suspensions with an average particle size distribution in the range of less than 250 nm, making individual particles invisible to the naked eye, and 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 suspensions described herein allow clobetasol propionate to effectively penetrate tissues from the high surface area nanoparticles upon surface application or injection. The nanoparticle formulations described herein are designed to optimally deliver a therapeutic amount of clobetasol propionate to the target tissue. Additionally, these aqueous spray formulations are compatible with damaged tissues with exudate when ointments, lotions, and / or creams are not available. As an injectable formulation, the suspension of clobetasol propionate nanoparticles described herein allows for the injection of more concentrated drug in smaller volumes and provides an extended duration of action.

[0098] Compositions of nanoparticle suspensions in spray or injectable formulations In another embodiment, this document describes 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, an injectable formulation is described herein. This injectable formulation can be injected into tendons / ligaments, synovial spaces, or intra-articular areas to treat diseases or injuries without the negative effects of conventional ointments / lotions.

[0100] In another embodiment, a nanoparticle suspension formulation of clobetasol propionate in the form of a spray, droplets, mist, aerosol, or injection is prepared as a sterile liquid 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 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 embodiment, 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, surfactantin, 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 ranging from about 0.01% to about 2% w / v, or from 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 glycerol, 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 ranging from about 0.0% to about 0.5% w / v, more specifically, from 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] This paper unexpectedly found 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 C) of an active drug molecule such as clobetasol propionate at an equivalent dose. max In another embodiment, the aqueous suspension of nanoparticles comprising boric acid and EDTA described herein does not exhibit long-term therapeutic exposure loss to active pharmaceutical molecules such as clobetasol propionate and maintains a significant half-life in tissues.

[0114] The suspension formulations described herein optionally include preservatives. 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 are typically required 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 found here that, when combined with certain additional excipients, such as boric acid and EDTA, BAC levels can be minimized to avoid irritation and inflammation. Lower levels of BAC, when combined with boric acid and EDTA, maintain antimicrobial efficacy. It has been unexpectedly found that, when combined with boric acid and EDTA, BAC levels reduced to below 0.006% to around 0.004% or about 0.003% or less maintain antimicrobial efficacy and serve as an effective preservative for the formulations described herein.

[0115] In another embodiment, the local spray, droplet, aerosol, or injectable formulation of the clobetasol propionate nanoparticle suspension 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 combinations 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 in this paper that higher concentrations of methylcellulose, through the formulations described herein, improve the retention of drug molecules at local target tissue sites. In another embodiment, the aqueous suspension of nanoparticles comprising higher concentrations of methylcellulose, as described herein, provides higher tissue concentrations (e.g., peak concentration C) of active drug molecules such as clobetasol propionate at equivalent administered doses. max In another embodiment, the aqueous suspension of nanoparticles comprising a higher concentration of methylcellulose described herein provides longer therapeutic exposure to active drug molecules such as clobetasol propionate, as indicated by a longer half-life in target tissues.

[0119] In another embodiment, the local spray, droplet, aerosol, or injectable formulation of the clobetasol propionate nanoparticle suspension contains sodium citrate (e.g., trisodium citrate) at a concentration in the range of about 0.01% to about 0.8% w / v to adjust the pH of the nanosuspension to an appropriate range, such as about 4.5 to about 6.5.

[0120] The formulations described herein may also include more than one additional therapeutic compound, 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 activities of the other components. Illustrated therapeutic compounds, which may be used as part of a combination to treat burns, infected tenosynovitis, or infected arthritis, are 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), 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), triazoles (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, antimicrobial agents for treating infected tendons or joints include (but are not limited to) penicillins 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 may 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 containing clobetasol propionate nanoparticles 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, antioxidants (e.g., ascorbic acid, sorbic acid, or alpha-lipoic acid), and antimicrobial agents may be included. Other components, in addition to the therapeutically active ingredient and components that are the primary effectors for penetration into the skin, eyes, inner ear, epithelium, or synovium, may include components provided for aesthetic 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 can be formulated in combination with the aforementioned pharmaceutically acceptable carriers into 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 can be formulated as 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 can be formulated as a liquid form that can be injected into the tympanic cavity, or injected into a subject's keloid or hypertrophic scar, or injected into inflamed synovial spaces, tendon / ligament attachment points, or joints.

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

[0128] The formulations described herein can be in the form of a topical dosage form packaged in, for example, multipurpose or single-use packaging, including, for example, tubing, pumps, containers or bottles, vials, cans, jars, boxes, or pouches; or in the form of an injectable form packaged in, for example, multiple-use or single-use packaging or pre-filled syringes. Single-dose cartons and packages containing a once-daily dose or other suitable amount of the topical delivery formulation or injection can be prepared. Single-dose, unit-dose, and once-daily single-use containers of the 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 the 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] How to use In another embodiment, the administration period of therapeutic compounds including clobetasol propionate (e.g., aqueous suspensions containing nanoparticles of 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) 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. In another implementation, the suspension or cessation of application 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, bi-weekly, 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 clobetasol propionate nanoparticles disclosed herein for treating subjects with burn wounds 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 the suspension of nanoparticles containing clobetasol propionate disclosed herein for treating subjects suffering from abnormal wound healing 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 subjects 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 subjects suffering from tenosynovitis, tendinitis, enthesitis, or arthritis reduces inflammation of the tendon, ligament, or joint 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 (such as 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, administration 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 period of time. In this embodiment, the 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 period of time 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%.

[0143] In another embodiment, a suspension of clobetasol propionate nanoparticles is sprayed or dripped directly onto areas of skin, eyes, nasal and sinus mucosa, intrapulmonary airways, or tympanic membrane affected by disease and / or injury. In applying the formulations of the invention disclosed herein, the formulation itself is illustratively administered by dripping into the eyes or nose, spraying onto the skin, eyes, nasal and sinus mucosa, inhalation into the lungs, or application to the tympanic membrane, for example, using a spray or dropper bottle or another suitable device. Spray bottles can be pump-operated spray bottles, spray bottles, any type of inhaler, aerosol spray bottles, nebulizer bottles, metering devices, etc. Dropper bottles can deliver a predetermined approximate volume (e.g., approximately 50 µL per application) of droplets. The amount of formulation used is generally sufficient to cover the desired 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 a bandage with a moisture-proof cover. For eye burns, a protective shield can simply be a bandage to protect the 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 are also possible, including the use of delivery devices, but this is not necessary. External reservoirs for extended application of the formulation can also be used.

[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 keloids or hypertrophic scars affected by disease and / or injury. In administering the formulation disclosed herein, the formulation itself is injected, for example, using a syringe and needle. The amount of formulation used is typically minimal and sufficient to treat the disease and / or injury. More sophisticated administration methods may also be used, including the use of delivery devices, but this is not necessary. External reservoirs for extended administration of the formulation may also be employed. Without being bound by theory, it is conceivable herein that potent glucocorticoids (e.g., clobetasol propionate) reduce pathological scarring by decreasing inflammation and fibroblast activation to limit the synthesis of scar tissue-characteristic proteins (e.g., collagen), ultimately leading to the regression of hypertrophic scars or keloids.

[0145] The formulation can be administered once, once, or more frequently as needed, for example, once daily to once every hour (if necessary). The formulations disclosed herein can 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 while symptoms persist. Suitable applications of the formulation include, for example, once daily, twice, three times, four times, six times daily, eight times daily, or once every hour (if necessary). The formulations described herein can 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, tension, injectability, syringe injectability, compatibility, homogeneity, resuspension, 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] Example 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 construed as limiting any of the embodiments described herein, including those embodiments relating to the type and amount of components of a 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 is 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 is dispersed in an aqueous medium using various excipients illustratively described in Tables 1A, 1B, and 2.

[0150] Figure 1 A summary flow chart of the steps for generating an illustrative nanoparticle suspension of clobetasol propionate is shown. Step A involves mixing the active pharmaceutical ingredient (API) with an abrasive. Illustrative abrasives include sodium chloride, hydrogenated soy lecithin, and anhydrous citric acid. Step B involves grinding the mixed formulation with glycerol to produce particle size distribution D. 90 Milled clobetasol propionate nanoparticles smaller than 250 nm.

[0151] Step C involves using a high-shear homogenizer to disperse a mixture of clobetasol propionate nanoparticles with poloxamer 407 and polyvinyl alcohol into a suspension to prepare particle size distribution D. 90 A nanoparticle suspension smaller than 250 nm. In step D, a mixture is prepared and combined 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 tonicity is adjusted with glycerol, and water for injection (WFI) is added to a sufficient volume. In step E, the prepared suspension undergoes final redispersion and is then aseptically filtered to produce a final aqueous suspension of clobetasol propionate nanoparticles.

[0152] The nano-milling 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. It 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 injection into the tympanic cavity, keloids or scar tissue, synovial spaces, tendon / ligament attachment points, joints, or scars. The clobetasol propionate nanoparticles in the formulation effectively penetrate tissues upon surface application or injection to deliver therapeutically effective concentrations of clobetasol propionate to target tissues such as skin or eye burn wounds, nasal cavity, lungs, ear canals, inner ear, synovial spaces, tendon / ligament attachment points, joints, or scars. Aqueous sprays and droplets are advantageous for use with tissues exudating fluids, such as burn wounds or inflamed nasal and sinus mucosa and respiratory airways.

[0153] Tables 1A, 1B and 2 show the illustrative formulation composition.

[0154] Table 1. Illustrative composition of A-clobetasol propionate nanoparticle suspension formulation

[0155] % represents w / v (weight / volume), for example, g / dL.

[0156] QS = sufficient quantity Table 1. Illustrative composition of the suspension formulation of β-propionate clobetasol propionate nanoparticles

[0157] % represents w / v (weight / volume), for example, g / dL.

[0158] QS = sufficient quantity Table 2 - Illustrative composition of clobetasol propionate nanoparticle suspension formulation

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

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

[0161] On day 1, animals were anesthetized with ketamine and toluenethiazide, and the local anesthetic was applied to the study eye. To induce an ocular alkali burn, a circular filter paper (No. 1 Whatman; approximately 5 mm in diameter) was soaked in 1 M NaOH for approximately 10 seconds and then placed in the center of the cornea of ​​the study eye for approximately 20 seconds. After removing the filter paper, the ocular surface was immediately flushed with approximately 30 mL of balanced salt solution. Thirty minutes after ocular 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. Ocular examination, slit-lamp photography, OCT measurements, and surface fluorescein staining were performed immediately after flushing the alkali burn wound on day 1, and immediately on day 3 and day 7 before administration. Slit-lamp examination was used to assess corneal opacity, area of ​​corneal damage, 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 2By 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 (Fig. D). Fig. 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 a bright white area in the central cornea (top image, arrow).

[0163] Histological analysis confirmed that eyes treated with CPN 0.1% showed reduced corneal stromal findings (fibrosis, mononuclear cell infiltration, edema, and neovascularization) and a decreased incidence and severity of 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 in this article can be used for long-term improvement of visual acuity and visual sharpness following ocular alkali burns.

[0164] Example 3. Treatment of skin burn wounds In a porcine burn wound model (n=3 female Yorkshire crossbred pigs, 35 ± 10 kg), the efficacy of CPN 0.1% in reducing inflammation and granulation tissue formation was evaluated. On day 0, animals were sedated with tiletamine-zolazepam and then anesthetized with isoflurane. Ten full-thickness burn wounds, 2 cm in diameter, were created on the backs 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 debrided / excised with a 2 cm trephine saw, bandaged with a transparent film dressing (Tegaderm™), then bandaged with a blue absorbent pad, and finally wrapped with an elastic bandage around the torso. Buprenorphine (0.02 mg / kg, IM) was used to treat postoperative pain, 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 in the CPN 0.1% group; n = 10 wounds in the untreated control group). CPN 0.1% treatment began 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 a 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 wounds were assessed using the modified Draize scoring system to evaluate erythema and edema. The extent of granulation tissue was assessed using the following scoring system: a score of 1 indicates the absence of granulation tissue; a score of 2 indicates that granulation tissue partially covers the wound floor; a score of 3 indicates that granulation tissue completely covers the wound floor but does not fill the wound volume; and a score of 4 indicates that granulation tissue is present throughout the entire wound volume.

[0166] The results are shown in Figure 3In this study, 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. CPN 0.1% also reduced granulation tissue formation from day 7 to day 11, 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 scars 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 of 7 mm diameter were surgically created on the ventral side of both ears of each rabbit. CPN 0.1% treatment was initiated once daily for 3 weeks, 5 days a week, starting within 60 minutes of wound creation. The treatment consisted of applying 50 µL of CPN 0.1% to the wound, covering it with an 8 × 8 mm sterile filter paper, and then applying another 50 µL of CPN 0.1% to the filter paper. The wound was then bandaged with a round Band-Aid adhesive dressing, followed by a transparent film dressing (Tegaderm™). The untreated control wounds were bandaged in the exact same manner, except that no treatment was applied. Twice a week, the Dryz scoring system was used to assess inflammation in the wound, with erythema scores of 0 indicating no erythema, 1 indicating mild erythema, 2 indicating well-defined erythema, 3 indicating moderate to severe erythema, and 4 indicating severe erythema or eschar. Edema scores were 0 indicating no edema, 1 indicating mild edema, 2 indicating mild edema with well-defined borders, 3 indicating edema (elevation >1 mm), and 4 indicating 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 4During 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. Histological analysis on day 28 showed hypertrophic scarring in all wounds of 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. Clear evidence of hypertrophic scarring was present in untreated control wounds (top image, shaded box) and hypertrophic scarring was absent in wounds treated with 0.1% CPN (bottom image). The nanoparticle suspension formulation of clobetasol propionate described in this article significantly and substantially reduces and / or prevents abnormal hypertrophic scarring in wounds.

[0169] Example 5. Reduction or removal of abnormal hypertrophic scars The efficacy of intralesional injection of the nanoparticle suspension 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 (n=4 CPN 0.1% group; n=4 mediator group) were anesthetized with ketamine / toluidine and four full-thickness excision wounds of 7 mm diameter were surgically created on the ventral side of both ears. The wounds remained untreated for 20 days, at which point they closed and developed into hypertrophic raised scars. On days 21, 28, and 35, 0.1% CPN or the mediator (10 µL) was injected into the scars using a 32-gauge needle and a microsyringe pump (Hamilton). On day 40, the animals were euthanized and the wounds were 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 wounds, indicated by elevated 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 structure, and scar area compared to controls, resulting in the absence of hypertrophic scarring. This suggests that intralesional injection of the suspension of clobetasol propionate nanoparticles described herein can significantly reduce the size of abnormal hypertrophic scars in wounds.

[0171] Example 6. Treatment of tenosynovitis, tendinitis, enthesitis, and arthritis The efficacy of 0.1% CPN in reducing arthritis symptoms was evaluated in a rat model of collagen-induced arthritis (CIA). To induce the arthritis phenotype, male Lewis rats (n=20, 200–250 g) were subcutaneously injected at the base of the tail on day 0 with 200 µL of 1 mg / mL bovine type II collagen / incomplete Freund's adjuvant solution, followed by a booster injection of 100 µL on day 7. By days 28–42, the CIA model produced 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, either 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 a week using organ fill measurement. On day 15, the inflammation of the paws and joints in 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 a post-hoc test with Bonferroni). These effects persisted throughout the observation period. Rats treated with CPN 0.1% exhibited normal-looking paws 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. The rapid and significant reduction in paw swelling and joint and tendon inflammation by CPN 0.1% suggests that the suspension formulation of clobetasol propionate nanoparticles described herein may be effective in reducing inflammation around 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 clobetasol propionate nanoparticle suspension formulation 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 (IT) of 5 µL of either CPN 0.1% or the mediator. The IT injection was administered to animals fixed in a stereotactic device equipped with a microsyringe / microinfusion pump assembly. Following the IT injection, animals were held in place with the injected ear facing upward for 30 min to allow the administration suspension to contact the round window membrane and for clobetasol propionate to diffuse into the inner ear fluid.

[0174] One.5 h after IT injection, animals were subjected to single noise exposure in a soundproof chamber. Mice were exposed to noise in wire cages surrounded by ceramic loudspeakers, with the noise generated and filtered to 4.0–45.0 kHz. Mice were exposed to 110 dB once for 30 min. Two weeks after noise exposure, ABR hearing threshold assessment was performed, followed by euthanasia and cochlear harvesting for histological analysis of the auditory apparatus of the inner ear.

[0175] Histological analysis of the cochlea was used to compare the internal and external hair cell counts and the degree of preservation of their 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 disorders (tinnitus) The efficacy of IT injection of a suspension of clobetasol propionate nanoparticles described herein in reducing tinnitus was evaluated in a mouse model. For example, C57BL / 6J mice were tested using a sound-based avoidance detection (SBAD) paradigm (n=10 CPN 0.1% group; n=10 mediator group). Mice were trained in a shuttle box to elicit Go or No-Go performance 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 throughout the box were used to detect the animal's position. The Go test monitored motor, motivational, and learning / memory functions, while the No-Go test monitored tinnitus-like behavior. Both types of tests were always randomly assigned during each training and testing phase, with a 4-second interval between tests. Training phases began with a 2-minute acclimatization period, followed by 100 tests per day for a total of 30–40 minutes. In the Go test, animals were trained to move from one compartment to another as soon as any auditory stimulus was presented. The louvered door was closed when they moved to the other compartment. If they did not move through the blinds, they received a foot shock for 5 seconds after the sound stimulus began. In the No-Go test, animals were trained to remain in the compartment if no sound was delivered. If they moved through the blinds within 10 seconds, they received a shock, but the blinds remained open. For both the Go and No-Go tests, the shocks were turned off after the animal moved to another compartment or at the end of the test. The sound stimuli were presented randomly, and both the frequency and intensity varied.

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

[0178] After successfully completing SBAD training (90-100% correct test responses), mice were subjected to unilateral noise-induced trauma, resulting in tinnitus. On day 0 prior to 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 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 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 a Stomahesive™ (ConvaTec). Two hours later, the mice were placed in a sound-attenuating 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 post-noise exposure. At each time point, both the mediator and treatment groups showed few 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—that is, 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 (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. Showing very few errors (90-100% correct response) in the No-Go test indicates high efficacy in reducing noise-induced tinnitus. It is expected that IT injection of the suspension formulation of clobetasol propionate nanoparticles described herein will show a high percentage of correct responses, suggesting that this formulation may be suitable for treating tinnitus in subjects, including humans.

[0180] Example 9. Treatment of Allergic Rhinitis / Sinusitis The clobetasol propionate nanoparticle suspension described herein can be used to treat subjects suffering from allergic rhinitis. For example, a 30-year-old woman visits a clinic complaining of excessive nasal discharge, nasal itching, and difficulty breathing through her nose, which are not improved with conventional allergy treatments. The clinician observes the characteristic signs / symptoms of allergic rhinitis: nasal exudate, deep redness of the nasal mucosa, and significant swelling of the nasal and sinus mucosa. The clinician recognizes that conventional allergy treatments may not be effective in treating the subject's symptoms and signs, especially when significant fluid exudate is present. In this embodiment, the clinician uses a spray bottle to apply an aqueous suspension of clobetasol propionate nanoparticles to the nasal and sinus mucosa. The liquid suspension is 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 is reapplied once daily or more frequently for a period of one week or longer. After one week or longer, the subject returns to the clinic for evaluation. Subjects reported significant improvement in their allergic rhinitis symptoms and signs, and indicated to clinicians that the treatment reduced itching and difficulty breathing through their nose. Further observation by clinicians confirmed that the use of a suspension of clobetasol propionate nanoparticles resulted in faster resolution of rhinitis. This demonstrates that a suspension of clobetasol propionate nanoparticles is an effective, convenient, and comfortable treatment for allergic rhinitis.

[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 visits a clinic complaining of shortness of breath, chest tightness and pain, wheezing, and coughing. The clinician recognizes these symptoms as consistent with asthma and administers standard treatment to quickly relieve acute asthma symptoms. In this example, the clinician demonstrates to the subject how to use an inhaler to administer the aqueous suspension of the clobetasol propionate nanoparticles described herein to treat asthma. The liquid suspension is inhaled into the lungs once or more daily to treat asthma symptoms. After one week or more, the subject returns to the clinic for evaluation. The subject reports significant improvement in asthma symptoms and currently breathes freely without asthma symptoms. Further observation by the clinician confirms the effectiveness of clobetasol propionate in treating asthma. This demonstrates that the clobetasol propionate nanoparticle suspension is effective, convenient, and comfortable for treating asthma.

[0182] Example 11. Effect of methylcellulose concentration on tissue permeability The tissue penetration of a suspension of clobetasol propionate nanoparticles 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 a suspension of clobetasol propionate nanoparticles was instilled into the rabbit eye.

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

[0185] The clobetasol propionate nanoparticle suspension described herein provides a longer half-life after topical ocular application (i.e., the active ingredient clobetasol propionate retains its pharmacological activity in target tissues such as the conjunctiva). Furthermore, the clobetasol propionate nanoparticle suspension described herein provides a higher concentration of clobetasol propionate in target tissues at an equivalent dose of the active ingredient in the formulation (C0). max ) and treatment exposure.

[0186] Example 11. Effects of boric acid and EDTA on tissue permeability The tissue penetration of the clobetasol propionate nanoparticle suspension into the cornea was measured using a standard protocol. Following application of 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 after application of the formulation containing boric acid and disodium edetate (EDTA) as described herein (Table 4).

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

[0188] C max (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 in this article provides higher concentrations and therapeutic exposure of clobetasol propionate in target tissues such as the cornea at equivalent doses of the active ingredient. When presented with C max When the values ​​are calculated, the different doses of 0.05% and 0.1% are normalized.

[0190] To further describe the invention, all patents, patent publications, and other publications referenced and identified in this specification are individually and expressly incorporated herein by reference in their entirety. However, the referenced patents, patent publications, and other publications should not be construed as accepted prior art.

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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